Cycloalkyl amine compounds and uses thereof

ABSTRACT

Aminocycloalkyl compounds are disclosed. The compounds of the present invention may be incorporated in compositions and kits. The present invention also discloses a variety of in vitro and in vivo uses for the compounds and compositions, including the treatment of arrhythmia and the production of local analgesia and anesthesia.

This application is a 371 of PCT/CA00/00117 filed on Feb. 10, 2000 whichclaims the benefit of Provisional application Ser. No. 60/119,887 filedFeb. 12, 1999.

TECHNICAL FIELD

The present invention is generally directed toward cycloalkyl aminecompounds such as aminocycloalkyl ether compounds and aminocycloalkylester compounds, pharmaceutical compositions and kits containing thecycloalkyl amine compounds, and therapeutic uses thereof .

BACKGROUND OF THE INVENTION

Arrhythmia is a variation from the normal rhythm of the heart beat. Themajor cause of fatalities due to cardiac arrhythmias is the subtype ofarrhythmias known as ventricular fibrillation. Conservative estimatesindicate that, in the U.S. alone, approximately 300,000 individuals peryear suffer heart attacks. Approximately half of these die from suddencardiac death, the major cause of which is ventricular fibrillation.

Antiarrhythmic agents have been developed to prevent or alleviatecardiac arrhythmia. For example, Class I antiarrhythmic compounds havebeen used to treat supraventricular arrhythmias and ventriculararrhythmias. Treatment of ventricular arrhythmia is very important sincesuch an arrhythmia, especially ventricular fibrillation, can be fatal.Serious ventricular arrhythmias (ventricular tachycardia and ventricularfibrillation) occur most often in the presence of myocardial ischemiaand/or infarction. Ventricular fibrillation often occurs in the settingof acute myocardial ischemia, before infarction fully develops. Atpresent, lidocaine is the current drug of choice for prevention ofventricular fibrillation during acute ischemia. However, many Class Iantiarrhythmic compounds may actually increase mortality in patients whohave had a myocardial infarction. Therefore, there is a need in the artto identify new antiarrhythmic treatments, particularly treatments forventricular arrhythmias (as discussed above), as well as for atrialarrhythmias, which are also lacking suitable medical treatment. Thepresent invention fulfills this need, and further provides other relatedadvantages.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides cycloalkyl aminecompounds of formula (I), or a solvate or pharmaceutically acceptablesalt thereof:

wherein, independently at each occurrence,

-   -   n is selected from 1, 3 and 4;    -   Q is either O (oxygen) or —O—C(O);    -   X is selected from a direct bond, —C(R₆,R₁₄)—Y— and —C(R₁₃)═CH—;    -   Y is selected from a direct bond, O, S and C₁–C₄alkylene;    -   R₁₃ is selected from hydrogen, C₁–C₆alkyl, C₃–C₈cycloalkyl, aryl        and benzyl;    -   R₁ and R₂ are independently selected from hydrogen, C—C₈alkyl,        C₃–C₈alkoxyalkyl, C₁–C₈hydroxyalkyl, and C₇–C₁₂aralkyl; or    -   R₁ and R₂, when taken together with the nitrogen atom to which        they are directly attached in formula (I), form a ring denoted        by formula (II):        wherein the ring of formula (II) is formed from the nitrogen as        shown as well as three to nine additional ring atoms        independently selected from carbon, nitrogen, oxygen, and        sulfur; where any two adjacent ring atoms may be joined together        by single or double bonds, and where any one or more of the        additional carbon ring atoms may bear one or two substituents        selected from hydrogen, hydroxy, C₁–C₃hydroxyalkyl, oxo,        C₂–C₄acyl, C₁–C₃alkyl, C₂–C₄alkylcarboxy, C₁–C₃alkoxy,        C₁–C₂₀alkanoyloxy, or may form a spiro five- or six-membered        heterocyclic ring containing one or two heteroatoms selected        from oxygen and sulfur; and any two adjacent additional carbon        ring atoms may be fused to a C₃–C₈carbocyclic ring, and any one        or more of the additional nitrogen ring atoms may bear        substituents selected from hydrogen, C₁–C₆alkyl, C₂–C₄acyl,        C₂–C₄hydroxyalkyl and C₃–C₈galkoxyalkyl; or    -   R₁ and R₂, when taken together with the nitrogen atom to which        they are directly attached in formula (I), may form a bicyclic        ring system selected from 3-azabicyclo[3.2.2]nonan-3-yl,        2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl and        3-azabicyclo[3.2.0]heptan-3-yl;    -   R₃ and R₄ are independently attached to the cycloalkyl ring        shown in formula (I) at other than the 1 and 2 positions and are        independently selected from hydrogen, hydroxy, C₁–C₆alkyl and        C₁–C₆alkoxy, and, when both R₃ and R₄ are attached to the same        cycloalkyl ring atom, may together form a spiro five- or        six-membered heterocyclic ring containing one or two heteroatoms        selected from oxygen and sulfur;    -   R₅, R₆ and R₁₄ are independently selected from hydrogen,        C₁–C₆alkyl, aryl and benzyl, or R₆ and R₁₄, when taken together        with the carbon to which they are attached, may form a spiro        C₃–C₅cycloalkyl;    -   A is selected from C₅–C₁₂alkyl, a C₃–C₁₃carbocyclic ring, and        ring systems selected from formulae (III), (IV), (V),        (VI), (VII) and (VIII):        where R₇, R₈ and R₉ are independently selected from bromine,        chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl,        methanesulfonamido, nitro, sulfamyl, trifluoromethyl,        C₂–C₇alkanoyloxy, C₁–C₆alkyl, C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl,        C₁–C₆thioalkyl, aryl and N(R₁₅,R₁₆) where R₁₅ and R₁₆ are        independently selected from hydrogen, acetyl, methanesulfonyl        and C₁–C₆alkyl;        and        where R₁₀ and R₁₁ are independently selected from bromine,        chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl,        methanesulfonamido, nitro, sulfamyl, trifluoromethyl,        C₂–C₇alkanoyloxy, C₁–C₆alkyl, C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl,        C₁–C₆thioalkyl, and N(R₁₅,R₁₆) where R₁₅ and R₁₆ are        independently selected from hydrogen, acetyl, methanesulfonyl,        and C₁–C₆alkyl;        where R₁₂ is selected from bromine, chlorine, fluorine, carboxy,        hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro,        sulfamyl, trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl,        C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, and N(R₁₅,R₁₆)        where R₁₅ and R₁₆ are independently selected from hydrogen,        acetyl, methanesulfonyl, and C₁–C₆alkyl; and Z is selected from        CH, CH₂, O, N and S, where Z may be directly bonded to “X” as        shown in formula (I) when Z is CH or N, or Z may be directly        bonded to R₁₇ when Z is N, and R₁₇ is selected from hydrogen,        C₁–C₆alkyl, C₃–C₈cycloalkyl, aryl and benzyl;        including isolated enantiomeric, diastereomeric and geometric        isomers thereof, and mixtures thereof.

In other embodiments, the present invention provides a composition ormedicament that includes a compound according to formula (I) incombination with a pharmaceutically acceptable carrier, diluent orexcipient, and further provides a method for the manufacture of acomposition or medicament that contains a compound according to formula(I).

In other embodiments, the present invention provides pharmaceuticalcompositions that contain at least one compound of formula (I) in anamount effective to treat a disease or condition in a warm-bloodedanimal suffering from or having the disease or condition, and/or preventa disease or condition in a warm-blooded animal that would otherwiseoccur, and further contains at least one pharmaceutically acceptablecarrier, diluent or excipient. The invention further provides formethods of treating a disease or condition in a warm-blooded animalsuffering from or having the disease or condition, and/or preventing adisease or condition from arising in a warm-blooded animal, wherein atherapeutically effective amount of a compound of formula (I), or acomposition containing a compound of formula (I) is administered to awarm-blooded animal in need thereof. The diseases and conditions towhich the compounds, compositions and methods of the present inventionhave applicability are as follows: arrhythmia, diseases of the centralnervous system, convulsions, epileptic spasms, depression, anxiety,schizophrenia, Parkinson's disease, respiratory disorders, cysticfibrosis, asthma, cough, inflammation, arthritis, allergies,gastrointestinal disorders, urinary incontinence, irritable bowelsyndrome, cardiovascular diseases, cerebral or myocardial ischemias,hypertension, long-QT syndrome, stroke, migraine, ophthalmic diseases,diabetes mellitus, myopathies, Becker's myotonia, myasthenia gravis,paramyotonia congentia, malignant hyperthermia, hyperkalemic periodicparalysis, Thomsen's myotonia, autoimmune disorders, graft rejection inorgan transplantation or bone marrow transplantation, heart failure,hypotension, Alzheimer's disease or other mental disorder, and alopecia.

In another embodiment, the present invention provides a pharmaceuticalcomposition containing an amount of a compound of formula (I) effectiveto produce local analgesia or anesthesia in a warm-blooded animal inneed thereof, and a pharmaceutically acceptable carrier, diluent, orexcipient. The invention further provides a method for producing, localanalgesia or anesthesia in a warm-blooded animal which includesadministering to a warm-blooded animal in need thereof an effectiveamount of a compound of formula (I) or a pharmaceutical compositioncontaining a compound of formula (I). These compositions and methods maybe used to relieve or forestall the sensation of pain in a warm-bloodedanimal.

In another embodiment, the present invention provides a pharmaceuticalcomposition containing an amount of a compound of formula (I) effectiveto enhance the libido in a warm-blooded animal in need thereof, and apharmaceutically acceptable carrier, diluent, or excipient. Theinvention further provides a method for enhancing libido in awarm-blooded animal which includes administering to a warm-bloodedanimal in need thereof an effective amount of a compound of formula (I)or a pharmaceutical composition containing a compound of formula (I).These compositions and methods may be used, for example, to treat asexual dysfunction, e.g., impotence in males, and/or to enhance thesexual desire of a patient without a sexual dysfunction. As anotherexample, the therapeutically effective amount may be administered to abull (or other breeding stock), to promote increased semen ejaculation,where the ejaculated semen is collected and stored for use as it isneeded to impregnate female cows in promotion of a breeding program.

In another embodiment, the present invention provides a compound offormula (I) or composition containing a compound of formula (I), for usein methods for either modulating ion channel activity in a warm-bloodedanimal or for modulating ion channel activity in vitro.

These and other embodiments of the present invention will become evidentupon reference to the following drawings and detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a reaction sequence further described in Example 1,for preparing an aminocycloalkyl ether compound of the presentinvention.

FIGS. 2A and 2B illustrate a reaction sequence further described inExample 2 for preparing an aminocycloalkyl ether compound of the presentinvention.

FIG. 3 illustrates a procedure whereby either cis- or trans-compounds ofthe present invention may be prepared.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention is directed to cycloalkyl aminecompounds, pharmaceutical compositions containing the cycloalkyl aminecompounds, and various uses for the compound and compositions. Such usesinclude blockage of ion channels in vitro or in vivo, the treatment ofarrhythmias, the production of anesthesia, and other uses as describedherein. An understanding of the present invention may be aided byreference to the following definitions and explanation of conventionsused herein.

Definitions and Conventions

The compounds of the invention have either an ether oxygen atom (Q=O informula (I)) or the non-carbonyl ester oxygen atom (Q=—O—C(O) in formula(I)) at position 1 of a cycloalkyl ring, and an amine nitrogen atom atposition 2 of the cycloalkyl ring, where the cycloalkyl ring is eithercyclopentyl, cycloheptyl or cyclooctyl, with other positions numbered incorresponding order as shown below in structure (A) for cyclopentane,structure (B) for cycloheptane, and structure (C) for cyclooctane:

The bonds from the cycloalkyl ring to the 1-oxygen and 2-nitrogen atomsin the above formula may be relatively disposed in either a cis or transrelationship. In a preferred embodiment of the present invention, thestereochemistry of the amine and ether substituents of the cycloalkylring is either (R,R)-trans or (S,S)-trans. In another preferredembodiment the stereochemistry is either (R,S)-cis or (S,R)-cis.

In the formulae depicted herein, a bond to a substituent and/or a bondthat links a molecular fragment to the remainder of a compound may beshown as intersecting one or more bonds in a ring structure. Thisindicates that the bond may be attached to any one of the atoms thatconstitutes the ring structure, so long as a hydrogen atom couldotherwise be present at that atom. Where no particular substituent(s) isidentified for a particular position in a structure, then hydrogen(s) ispresent at that position. For example, compounds of the inventioncontaining the A—X—CH(R₁)-group where A equals formula (III)

are intended to encompass compounds having the group (D):

where the group (D) is intended to encompass groups wherein any ringatom that could otherwise be substituted with hydrogen, may instead besubstituted with either R₇, R₈ or R₉, with the proviso that each of R₇,R₈ and R₉ appears once and only once on the ring. Ring atoms that arenot substituted with any of R₇, R₉ or R₉ are substituted with hydrogen.In those instances where the invention specifies that a non-aromaticring is substituted with more than one R group, and those R groups areshown connected to the non-aromatic ring with bonds that bisect ringbonds, then the R groups may be present at different atoms of the ring,or on the same atom of the ring, so long as that atom could otherwise besubstituted with a hydrogen atom.

Likewise, where the invention specifies compounds containing theA—X—CH(R₅)— group where A equals the aryl group (VI)

the invention is intended to encompass compounds wherein —X—CH(R₅)— isjoined through X to the aryl group (VI) at any atom which forms the arylgroup (VI) so long as that atom of group (VI) could otherwise besubstituted with a hydrogen atom. Thus, there are seven positions(identified with the letters “a” through “g”) in structure (VI) wherethe —X—CH(R₅)— group could be attached, and it is attached at one ofthose seven positions. The R₁₂ group would occupy one and only one ofthe remaining six positions, and hydrogen atoms would be present in eachof the five remaining positions. It is to be understood that when Zrepresents a divalent atom, e.g., oxygen or sulfur, then Z cannot bedirectly bonded to —X—CH(R₅)—.

When the invention specifies the location of an asymmetric divalentradical, then that divalent radical may be positioned in any possiblemanner that provides a stable chemical structure. For example, forcompounds containing the A—X—CH(R₅)— group where X is C(₁₄,R₁₆)—Y—, theinvention provides compounds having both the A—C(R₁₄,R₁₆)—Y—CH(R₅)— andA—Y—C(R₁₄,R₆)—CH(R₅)— groups.

A wavy bond from a substituent to the central cycloalkyl ring indicatesthat that group may be located on either side of the plane of thecentral ring.

The compounds of the present invention contain at least two asymmetriccarbon atoms and thus exist as enantiomers and diastereomers. Unlessotherwise noted, the present invention includes all enantiomeric anddiastereomeric forms of the aminocycloalkyl ether compounds of theinvention. Pure stereoisomers, mixtures of enantiomers and/ordiastereomers, and mixtures of different compounds of the invention areincluded within the present invention. Thus, compounds of the presentinvention may occur as racemates, racemic mixtures and as individualdiastereomers, or enantiomers with all isomeric forms being included inthe present invention. A racemate or racemic mixture does not imply a50:50 mixture of stereoisomers.

The phrase “independently at each occurrence” is intended to mean (i)when any variable occurs more than one time in a compound of theinvention, the definition of that variable at each occurrence isindependent of its definition at every other occurrence; and (ii) theidentity of any one of two different variables (e.g., R₁ within the setR₁ and R₂) is selected without regard the identity of the other memberof the set. However, combinations of substituents ard/or variables arepermissible only if such combinations result in stable compounds.

In accordance with the present invention and as used herein, thefollowing terms are defined to have following meanings, unlessexplicitly stated otherwise:

“Acid addition salts” refers to those salts which retain the biologicaleffectiveness and properties of the free bases and which are notbiologically or otherwise undesirable, formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or organic acids such as acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and thelike.

“Acyl” refers to branched or unbranched hydrocarbon fragments terminatedby a carbonyl —(C═O)— group containing the specified number of carbonatoms. Examples include acetyl [CH₃C(O)—, a C₂acyl] and propionyl[CH₃CH₂C(O)—, a C₃acyl].

“Alkanoyloxy” refers to an ester substituent wherein the non-carbonyloxygen is the point of attachment to the molecule. Examples includepropanoyloxy [(CH₃CH₂C(O)—O—, a C₃alkanoyloxy] and ethanoyloxy[CH₃C(O)—O—, a C₂alkanoyloxy].

“Alkoxy” refers to an O-atom substituted by an alkyl group, for example,methoxy [—OCH₃, a C₁alkoxy].

“Alkoxyalkyl” refers to a alkylene group substituted with an alkoxygroup. For example, methoxyethyl [CH₃OCH₂CH₂—] and ethoxymethyl(CH₃CH₂OCH₂—] are both C₃alkoxyalkyl groups.

“Alkoxycarbonyl” refers to an ester substituent wherein the carbonylcarbon is the point of attachment to the molecule. Examples includeethoxycarbonyl [CH₃CH₂OC(O)—, a C₃alkoxycarbonyl] and methoxycarbonyl[CH₃OC(O)—, a C₂alkoxycarbonyl].

“Alkyl” refers to a branched or unbranched hydrocarbon fragmentcontaining the specified number of carbon atoms and having one point ofattachment. Examples include n-propyl (a C₃alkyl), iso-propyl (also aC₃alkyl), and t-butyl (a C₄alkyl).

“Alkylene” refers to a divalent radical which is a branched orunbranched hydrocarbon fragment containing the specified number ofcarbon atoms, and having two points of attachment. An example ispropylene [—CH₂CH₂CH₂—, a C₃alkylene].

“Alkylcarboxy” refers to a branched or unbranched hydrocarbon fragmentterminated by a carboxylic acid group [—COOH]. Examples includecarboxymethyl [HOOC—CH₂—, a C₂alkylcarboxy] and carboxyethyl[HOOC—CH₂CH₂—, a C₃alkylcarboxy].

“Aryl” refers to aromatic groups which have at least one ring having aconjugated pi electron system and includes carbocyclic aryl,heterocyclic aryl (also known as heteroaryl groups) and biaryl groups,all of which may be optionally substituted. Carbocyclic aryl groups aregenerally preferred in the compounds of the present invention, wherephenyl and naphthyl groups are preferred carbocyclic aryl groups.

“Aralkyl” refers to an alkylene group wherein one of the points ofattachment is to an aryl group. An example of an aralkyl group is thebenzyl group [C₆H₅CH₂—, a C₇aralkyl group].

“Cycloalkyl” refers to a ring, which may be saturated or unsaturated andmonocyclic, bicyclic, or tricyclic formed entirely from carbon atoms. Anexample of a cycloalkyl group is the cyclopentenyl group (C₅H₇—), whichis a five carbon (C₅) unsaturated cycloalkyl group.

“Carbocyclic” refers to a ring which may be either an aryl ring or acycloalkyl ring, both as defined above.

“Carbocyclic aryl” refers to aromatic groups wherein the atoms whichform the aromatic ring are carbon atoms. Carbocyclic aryl groups includemonocyclic carbocyclic aryl groups such as phenyl, and bicycliccarbocyclic aryl groups such as naphthyl, all of which may be optionallysubstituted.

“Heteroatom” refers to a non-carbon atom, where boron, nitrogen, oxygen,sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygenand sulfur being particularly preferred heteroatoms in the compounds ofthe present invention.

“Heteroaryl” refers to aryl groups having from 1 to 9 carbon atoms andthe remainder of the atoms are heteroatoms, and includes thoseheterocyclic systems described in “Handbook of Chemistry and Physics,”49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co.,Cleveland, Ohio. See particularly Section C, Rules for Naming OrganicCompounds, B. Fundamental Heterocyclic Systems. Suitable heteroarylsinclude furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl,imidazolyl, and the like.

“Hydroxyalkyl” refers to a branched or unbranched hydrocarbon fragmentbearing an hydroxy (—OH) group. Examples include hydroxymethyl (—CH₂OH,a C₁hydroxyalkyl) and 1-hydroxyethyl (—CHOHCH₃, a C₂hydroxyalkyl).

“Thioalkyl” refers to a sulfur atom substituted by an alkyl group, forexample thiomethyl (CH₃S—, a C₁thioalkyl).

“Modulating” in connection with the activity of an ion channel meansthat the activity of the ion channel may be either increased ordecreased in response to administration of a compound or composition ormethod of the present invention. Thus, the ion channel may be activated,so as to transport more ions, or may be deactivated or blocked, so thatfewer or no ions, respectively, are transported by the channel.

“Pharmaceutically acceptable carriers” for therapeutic use are wellknown in the pharmaceutical art, and are described, for example, inRemingtons Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaroedit. 1985). For example, sterile saline and phosphate-buffered salineat physiological pH may be used. Preservatives, stabilizers, dyes andeven flavoring agents may be provided in the pharmaceutical composition.For example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid may be added as preservatives. Id. at 1449. In addition,antioxidants and suspending agents may be used. Id.

“Pharmaceutically acceptable salt” refers to salts of the compounds ofthe present invention derived from the combination of such compounds andan organic or inorganic acid (acid addition salts) or an organic orinorganic base (base addition salts). The compounds of the presentinvention may be used in either the free base or salt forms, with bothforms being considered as being within the scope of the presentinvention.

The “therapeutically effective amount” of a compound of the presentinvention will depend on the route of administration, the type ofwarm-blooded animal being treated, and the physical characteristics ofthe specific warm-blooded animal under consideration. These factors andtheir relationship to determining this amount are well known to skilledpractitioners in the medical arts. This amount and the method ofadministration can be tailored to achieve optimal efficacy but willdepend on such factors as weight, diet, concurrent medication and otherfactors which those skilled in the medical arts will recognize.

Compositions described herein as “containing a compound of formula (I)”encompass compositions that contain more than one compound of formula(I).

Compounds of the Present Invention

The compounds of the present invention are amines which may berepresented by formula (I):

Compounds of formula (I) are cycloalkylamines such as aminocycloalkylethers and aminocycloalkyl esters. More specifically, theseaminocycloalkyl ethers and aminocycloalkyl esters are substituted atposition 2 of a cycloalkyl ring with an amine group —NR₁R₂. The C-1position is either an ether (Q=O in formula (I)) or an ester function(Q=—O—C(O) in formula (I)). The cycloalkyl ring may also be substitutedwith additional substituents (designated as R₃ and R₄) as described inmore detail below. In formula (I), n is selected from 1, 3 and 4, andrepresents a number of carbon atoms such that when n equals 1, the ringshown in Formula (I) is a substituted cyclopentane (i.e., a cyclopentylgroup), when n equals 3, the ring shown in Formula (1) is a substitutedcycloheptane (i.e., a cycloheptyl group), and when n equals 4, the ringshown in Formula (I) is a substituted cyclooctane (i.e., a cyclooctylgroup). Examples of specific embodiments of compounds represented byformula (I) are described below.

Depending upon the selection of substituents R₁ and R₂, the compounds offormula (I) may be primary, secondary, or tertiary amines (i.e., both R₁and R₂ are hydrogen, only one of R₁ and R₂ is hydrogen, or neither of R₁and R₂ are hydrogen, respectively). Where the amine is tertiary, it maybe a cyclic amine. Amine substituents R₁ and R₂ may be independentlyselected from substituents which include hydrogen, alkyl groupscontaining from one to eight carbon atoms (i.e., C₁–C₈alkyl),alkoxyalkyl groups containing from three to eight carbon atoms (i.e.,C₃–C₈alkoxyalkyl), alkyl groups containing from one to eight carbonatoms where one of the carbon atoms is substituted with a hydroxyl group(i.e., C₁–C₈hydroxyalkyl), and aralkyl groups containing from seven totwelve carbon atoms (i.e., C₇–C₁₂aralkyl).

Alternatively, R₁ and R₂, when taken together with the nitrogen atom towhich they are directly attached in formula (I), may form a ring denotedby formula (II):

wherein the ring of formula (II) is formed from the nitrogen as shown aswell as three to nine additional ring atoms independently selected fromcarbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atomsmay be joined together by single or double bonds, and where any one ormore of the additional carbon ring atoms may be substituted with one ortwo substituents selected from hydrogen, hydroxy, C₁–C₃hydroxyalkyl,oxo, C₂–C₄acyl, C₁–C₃alkyl, C₂–C₄alkylcarboxy, C₁–C₃alkoxy,C₁–C₂₀alkanoyloxy, or may be substituted to form a spiro five- orsix-membered heterocyclic ring containing one or two heteroatomsselected from oxygen and sulfur (e.g., an acetal, thioacetal, ketal, orthioketal group); and any two adjacent additional carbon ring atoms maybe fused to a C₃–C₈carbocyclic ring, and any one or more of theadditional nitrogen ring atoms may be substituted with substituentsselected from hydrogen, C₁–C₆alkyl, C₂–C₄acyl, C₂–C₄hydroxyalkyl andC₃–C₈alkoxyalkyl. Examples of substituents containing a fused ringsystem include the perhydroindolyl and 1,2,3,4-tetrahydroisoquinolinylgroups.

In connection with the ring of formula (II), any two adjacent ring atomsmay be joined together by single or double bonds. Thus, the ring offormula (II) may be saturated or unsaturated, and an unsaturated ringmay contain one, or more than one, sites of unsaturation. In otherwords, the ring of formula (II) may contain one or more double bonds, itbeing understood, however, that the unsaturated ring of formula (II) ischemically stable.

Alternatively, R₁ and R₂, when taken together with the 2-amino nitrogenof formula (I), may complete a bicyclic ring. Bicyclic rings include,for example, 3-azabicyclo[3.2.2]nonane, 2-azabicyclo[2.2.2]octane,3-azabicyclo[3.1.0]hexane, and 3-azabicyclo[3.2.0]heptane. For thesederivatives, the C-2 substituents of the cycloalkyl ethers of formula(I) are the following groups: 3-azabicyclo[3.2.2]nonan-3-yl,2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl, and3-azabicyclo[3.2.0]heptan-3-yl.

Preferably for formula (II), R₁ and R₂, when taken together, containonly a single heteroatom. Preferred heteroatoms include nitrogen, oxygenand sulfur. An example of a ring in which R₁ and R₂ together include anoxygen heteroatom is the morpholinyl group. An example of a ring whereR₁ and R₂ together include a second nitrogen heteroatom is thepiperazinyl group.

Cycloalkyl substituents R₃ and R₄ may be independently attached to anyof the ring positions except positions 1 and 2 (e.g., both R₃ and R₄ maybe attached to the same ring position or each attached to different ringpositions). R₃ and R₄ are independently selected from hydrogen, hydroxy,C₁–C₆alkyl, and C₁–C₆alkoxy, and, when both R₃ and R₄ are attached tothe same cycloalkyl ring atom, may together form a spiro five- orsix-membered heterocyclic ring containing one or two heteroatomsselected from oxygen and sulfur. Preferred heterocyclic substituentscontain either a single oxygen or a single sulfur ring atom.

Depending upon the identity of X, the ether or ester sidechain,—CH(R₅)—X—A, in formula (I) may take several forms. For example, acompound of formula (I) may have X as a —C(R₆,R₁₄)—Y— group, where Y maybe any of a direct bond, an oxygen atom (O), a sulfur atom (S) or aC₁–C₄alkylene group. R₆ and R₁₄ are independently selected fromhydrogen, C₁–C₆alkyl, aryl and benzyl, or R₆ and R₁₄, when takentogether with the carbon to which they are attached, may form a spiroC₃–C₅cycloalkyl. Thus, compounds of the invention include compounds offormula (I) where R₆ and R₁₄ are hydrogen and Y is a direct bond, suchthat X may be CH₂.

Alternatively, X may be an alkenylene moiety, e.g., a cis-ortrans-alkenylene moiety, C(R₁₃)═CH, where R₁₃ may be any of hydrogen,C₁–C₆alkyl, C₃–C₈cycloalkyl, aryl or benzyl. For compounds of formula(I) where X is an alkenylene moiety, X is preferably a trans-alkenylenemoiety.

Alternatively, X may be a direct bond. Independent of the selections forA, X and other variables, R₅ is selected from hydrogen, C₁–C₆alkyl, aryland benzyl.

Ether or ester sidechain component A is generally a hydrophobic moiety.Typically, a hydrophobic moiety is comprised of non-polar chemicalgroups such as hydrocarbons or hydrocarbons substituted with halogens orethers or heterocyclic groups containing nitrogen, oxygen, or sulfurring atoms. Suitable hydrocarbons are C₅–C₁₂alkyl and C₃–C₁₃carbocyclicrings. Particularly preferred cyclic hydrocarbons include selectedaromatic groups such as phenyl, 1-naphthyl, 2-naphthyl, indenyl,acenaphthyl, and fluorenyl and are represented by formulae (III), (IV),(V), (VI), (VII), or (VIII) respectively.

A suitable “A” group within the compounds of the present invention is aphenyl ring represented by formula (III):

where R₇, R₈ and R₉ are independently selected from bromine, chlorine,fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,nitro, sulfamyl, trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl,C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, aryl and N(R₁₅,R₁₆)where R₁₅ and R₁₆ are independently selected from hydrogen, acetyl,methanesulfonyl, and C₁–C₆alkyl.

For compounds of formula (I) where X is a direct bond or CH₂, at leastone of R₇, R₈ and R₉ is preferably selected from amine (—NR₁₅R₁₆, whereR₁₅ and R₁₆ are independently hydrogen, acetyl, methanesulfonyl, andC₁–C₆alkyl), bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy,hydroxymethyl, nitro, trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl,C₁–C₆alkoxy, C₂–C₇alkylcarbonyl, C₁–C₆thioalkyl or aryl groups. Forcompounds of formula (I) when X is CH═CH, and R₃ and R₄ are hydrogen, atleast one of R₇, R₈ and R₉ is preferably a substituent other thanhydrogen.

Other suitable “A” groups in compounds of the present invention are1-naphthyl groups as represented by formula (IV):

where R₁₀ and R₁₁ are independently selected from bromine, chlorine,fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,nitro, sulfamyl, trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl,C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, and N(R₁₅,R₁₆) whereR₁₅ and R₁₆ are independently selected from hydrogen, acetyl,methanesulfonyl, and C₁–C₆alkyl.

Other suitable “A” groups in compounds of the present invention are2-naphthyl group as represented by formula (V):

where R₁₀ and R₁₁ are independently selected from bromine, chlorine,fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,nitro, sulfamyl, trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl,C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, and N(R₁₅,R₁₆) whereR₁₅ and R₁₆ are independently selected from hydrogen, acetyl,methanesulfonyl, and C₁–C₆alkyl, as defined above.

Other suitable “A” groups in compounds of the present invention arearomatic groups represented by formula (VI):

where R₁₂ is selected from bromine, chlorine, fluorine, carboxy,hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyltrifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl, C₁–C₆alkoxy,C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, and N(R₁₅,R₁₆) where R₁₅ and R₁₆are independently selected from hydrogen, acetyl, methanesulfonyl, andC₁–C₆alkyl; and Z is selected from CH, CH₂, O, N and S, where Z may bedirectly bonded to “X” as shown in formula (I) when Z is CH or N, or Zmay be directly bonded to R₁₇ when Z is N, and R₁₇ is selected fromhydrogen, C₁–C₆alkyl, C₃–C₈cycloalkyl, aryl and benzyl.

The aryl groups of formula (VI) are derivatives of indene, indole,benzofuran, and thianaphthene when Z is methylene, nitrogen, oxygen, andsulfur, respectively. Preferred heterocyclic groups of formula (VI)include indole where Z is NH, benzofuran where Z is O, and thianaphthenewhere Z is S. As described below, in a preferred embodiment, Z is O, Sor N—R₁₇, and in a particularly preferred embodiment Z is O or S.

Another suitable “A” group in compounds of the present invention areacenaphthyl groups as represented by formula (VII):

Still another suitable “A” group in compounds of the present inventionis the fluorenyl group represented by formula (VIII):

Preferably, ether or ester sidechain component A is an acenaphthyl orfluorenyl group only when X is a direct bond or CH₂. In furtherpreferred embodiments, the acenaphthyl group is a 1-acenaphthyl group,and the fluorenyl group is a 9-fluorenyl group.

As mentioned above, the present invention provides aminocycloalkylethers and aminocycloalkyl esters represented by formula (I). In apreferred embodiment X is (CH₂)—Y. For these embodiments, Y ispreferably a direct bond, an oxygen atom, or a sulfur atom. In aparticularly preferred embodiment, Y is a direct bond or an oxygen atom.In another preferred embodiment Y is a direct bond and X is C(R₆,R₁₄),where R₆ and R₁₄ are as defined above. In another preferred embodiment,where X is C(R₁₃)═CH, R₁₃ is a hydrogen atom. For these embodiments, R₃and R₄ are preferably independently attached to the cycloalkyl ring atthe 4- or 5-positions.

The following are further preferred compounds of the present invention:

Outline of Method of Preparation of Compounds of the Invention

The aminocycloalkyl ether compounds and the aminocycloalkyl estercompounds of the present invention contain amino and ether or estersidechains disposed in a 1,2 arrangement on a cycloalkyl ring.Accordingly, the amino and ether or ester sidechains may be disposed ineither a cis or trans relationship with respect to the plane of thecycloalkyl ring. The present invention provides synthetic methodologywhereby cis or trans compounds may be prepared.

Trans compounds of the present invention may be prepared in analogy withknown synthetic methodology (see, e.g., Shanklin, Jr. et al., U.S. Pat.No. 5,130,309). FIG. 1 outlines the preparation of a trans compound ofthe invention, which is more fully described in Example 1. As outlinedin FIG. 1, the preparation of a trans compound of the invention may becarried out by a four step procedure.

In a first step (equation i) in FIG. 1), cyclopentene epoxide undergoesa ring-opening reaction with an amine. See, e.g., Szmuszkovicz, U.S.Pat. No. 4,145,435. While the reaction can occur at room temperature,typically elevated temperature is preferred in order to drive thereaction to completion in a commercially desirable length of time. Thereaction is typically conducted at reflux in a solvent, such as water.Equimolar amounts of the amine and cyclopentene epoxide typicallyprovide trails-1hydroxy 2-amino cyclopentane. A wide variety of aminecompounds and substituted cyclopentene oxides may be employed in thisgeneral reaction. FIG. 1 shows an example in which morpholine is reactedwith cyclopentene oxide. For amines or cyclopentene epoxides substitutedwith other reactive functional groups, appropriate protection groups areintroduced prior to step i). Suitable protective groups are set forthin, for example, Greene, “Protective Groups in Organic Chemistry”, JohnWiley & Sons, New York N.Y. (1991).

In a second step (equation ii) in FIG. 1) the hydroxy group derived fromthe epoxide is activated or converted into a good leaving group. Theleaving group illustrated in FIG. 1 is a mesylate which is preferred.However, the hydroxy group could be converted into other leaving groupsaccording to procedures well known in the art. In a typical reaction,the aminocyclopentanol compound is treated with methanesulfonyl chloridein the presence of a base, such as triethylamine as shown in FIG. 1. Thereaction is satisfactorily conducted at about 0° C. An excess of themethanesulfonyl chloride, relative to the aminocyclopentanol, istypically preferred for complete conversion of the more valuableaminocyclopentanol. For some other aminocyclopentanol compounds, it maybe necessary to introduce appropriate protection groups prior to stepii) being performed. Suitable protecting groups are set forth in, forexample, Greene, “Protective Groups in Organic Chemistry”, John Wiley &Sons, New York N.Y. (1991).

In a third step (equation iii) in FIG. 1) an alcohol is reacted with astrong base to provide an alkoxide salt. Conversion of an alcohol to analkoxide (also known as an alcoholate) using strong base is a reactionthat will work with a wide variety of hydroxy-containing compounds. Insome instances, the alcohol may have other reactive functional groupsthat are desirably protected prior to contact of the alcohol with strongbase. Suitable protecting groups are set forth in, for example, Greene,“Protective Groups in Organic Chemistry”, John Wiley & Sons, New YorkN.Y. (1991). Such alcohols are either commercially available or may beobtained by procedures described in the art or adapted therefrom, wheresuitable procedures may be identified through the Chemical Abstracts andIndices therefor, as developed and published by the American ChemicalSociety.

In a fourth step (equation iv) in FIG. 1), the alcoholate from iii) isreacted with the activated aminocyclopentanol from step ii) to give theether adduct. Thus, unless protective groups must be removed, compoundsof the present invention may be prepared by reacting an activated formof the appropriate 1,2-aminocycloalkanol (1 mol) with an alcoholate(1.25 mol) prepared by treatment of the selected alcohol (1.25 mol)with, for example, sodium hydride (1.3 mol). The 1,2-aminocyclopentanol(1 mol) can be activated by forming the corresponding mesylate, in thepresence of methanesulfonyl chloride (1.25 mol) and triethylamine (1.5mol). The mesylate is added quickly to the alcoholate, in a suitablesolvent such as dimethylformamide. The reaction temperature is monitoredcarefully in order to avoid undesired side-reactions such asβ-elimination. In general, a reaction temperature of 80–90° C. for 2hours is adequate to form compounds of the invention. When the reactionhas proceeded to substantial completion, the desired product isrecovered from the reaction mixture by conventional organic chemistrytechniques, and is purified generally by column chromatography followedby recrystallisation. Protective groups may be removed at theappropriate stage of the reaction sequence. Suitable methods are setforth in, for example, Greene, “Protective Groups in Organic Chemistry”,John Wiley & Sons, New York N.Y. (1991).

The reaction sequence described above (and shown in FIG. 1) generatesthe aminocycloalkyl ether as the free base. The pure enantiomeric formscan be obtained by preparative chiral HPLC. The free base may beconverted, if desired, to the monohydrochloride salt by knownmethodologies, and subsequently, if desired, to other acid additionsalts by reaction with inorganic or organic salts. Acid addition saltscan also be prepared metathetically by reacting one acid addition saltwith an acid which is stronger than that of the anion of the initialsalt.

It should be noted that aminocycloalkyl ester compounds of the presentinvention (formula (I) where Q is —O—C(O)—), can be prepared by standardacylation of the aminocycloalkyl alcohol formed in equation i) ofFIG. 1. This is analogous to methods described in U.S. Pat. No.5,637,583 and references cited therein.

Alternatively, cis or trans compounds of the invention may be preparedaccording to the chemistry outlined in FIG. 3. As shown in FIG. 3,2-aminocyclopentanones may be prepared by Swern oxidation of thecorresponding trans-1,2-aminocyclopentanol compounds (which may beprepared as described above) using oxalyl chloride/dimethyl sulfoxide(see, e.g., Synthesis 1980, 165). Subsequent reduction of theaminocyclopentanone with lithium aluminum hydride or sodium borohydrideprovides a mixture of cis- and trans-aminocyclopentanols. The mixture ofaminoalcohols may be esterified with an appropriate carboxylic acid byazeotropic distillation in toluene in the presence of a catalytic amountof p-toluenesulfonic acid, to provide a diastereomeric mixture of cis-and trans-ester compounds of the present invention. The mixture ofdiastereomeric esters can be separated by preparative chromatography byone of ordinary skill in the art. The racemic cis- or trans ester couldthen be reduced with sodium borohydride in the presence of Lewis acid tothe corresponding racemic cis- or trans-ether (see, e.g., J. Org. Chem.25:875, 1960 and Tetrahedron 18:953, 1962). The racemic cis-ether can beresolved by preparative chiral HPLC as discussed above for thetrans-compound.

The synthetic procedures described herein, especially when taken withthe general knowledge in the art, provide sufficient guidance to thoseof ordinary skill in the art to perform the synthesis, isolation, andpurification of the compounds of the present invention.

Compositions and Modes of Administration

In another embodiment, the present invention provides compositions whichinclude a cycloalkylamine compound as described above in admixture orotherwise in association with one or more inert carriers, excipients anddiluents, as well as optional ingredients if desired. These compositionsare useful as, for example, assay standards, convenient means of makingbulk shipments, or pharmaceutical compositions. An assayable amount of acompound of the invention is an amount which is readily measurable bystandard assay procedures and techniques as are well known andappreciated by those skilled in the art. Assayable amounts of a compoundof the invention will generally vary from about 0.001 wt % to about 75wt % of the entire weight of the composition. Inert carriers include anymaterial which does not degrade or otherwise covalently react with acompound of the invention. Examples of suitable inert carriers arewater; aqueous buffers, such as those which are generally useful in HighPerformance Liquid Chromatography (HPLC) analysis; organic solvents suchas acetonitrile, ethyl acetate, hexane and the like (which are suitablefor use in in vitro diagnostics or assays, but typically are notsuitable for administration to a warm-blooded animal); andpharmaceutically acceptable carriers, such as physiological saline.

Thus, the present invention provides a pharmaceutical or veterinarycomposition (hereinafter, simply referred to as a pharmaceuticalcomposition) containing a cycloalkylamine compound as described above,in admixture with a pharmaceutically acceptable carrier, excipient ordiluent. The invention further provides a pharmaceutical compositioncontaining an effective amount of a cycloalkylamine compound asdescribed above, in association with a pharmaceutically acceptablecarrier.

The pharmaceutical compositions of the present invention may be in anyform which allows for the composition to be administered to a patient.For example, the composition may be in the form of a solid, liquid orgas (aerosol). Typical routes of administration include, withoutlimitation, oral, topical, parenteral, sublingual, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, epidural, intrasternal injectionor infusion techniques. Pharmaceutical composition of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a patient take the form of oneor more dosage units, where for example, a tablet, capsule or cachet maybe a single dosage unit, and a container of cycloalkylamine compound inaerosol form may hold a plurality of dosage units.

Materials used in preparing the pharmaceutical compositions should bepharmaceutically pure and non-toxic in the amounts used. The inventivecompositions may include one or more compounds (active ingredients)known for a particularly desirable effect. For instance, epinephrine maybe combined with an cycloalkyl amine compound of the invention, toprovide a composition useful to induce local anesthesia. It will beevident to those of ordinary skill in the art that the optimal dosage ofthe active ingredient(s) in the pharmaceutical composition will dependon a variety of factors. Relevant factors include, without limitation,the type of subject (e.g., human), the particular form of the activeingredient, the manner of administration and the composition employed.

In general, the pharmaceutical composition includes a cycloalkylaminecompound as described herein, in admixture with one or more carriers.The carrier(s) may be particulate, so that the compositions are, forexample, in tablet or powder form. The carrier(s) may be liquid, withthe compositions being, for example, an oral syrup or injectable liquid.In addition, the carrier(s) may be gaseous, so as to provide an aerosolcomposition useful in, e.g., inhalatory administration.

When intended for oral administration, the composition is preferably ineither solid or liquid form, where semi-solid, semi-liquid, suspensionand gel forms are included within the forms considered herein as eithersolid or liquid.

As a solid composition for oral administration, the composition may beformulated into a powder, granule, compressed tablet, pill, capsule,cachet, chewing gum, wafer, lozenges, or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following adjuvants may bepresent: binders such as syrups, acacia, sorbitol, polyvinylpyrrolidone,carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gumtragacanth or gelatin, and mixtures thereof; excipients such as starch,lactose or dextrins, disintegrating agents such as alginic acid, sodiumalginate. Primogel, corn starch and the like; lubricants such asmagnesium stearate or Sterotex; fillers such as lactose, mannitols,starch, calcium phosphate, sorbitol, methylcellulose, and mixturesthereof; lubricants such as magnesium stearate, high molecular weightpolymers such as polyethylene glycol, high molecular weight fatty acidssuch as stearic acid, silica, wetting agents such as sodium laurylsulfate, glidants such as colloidal silicon dioxide; sweetening agentssuch as sucrose or saccharin, a flavoring agent such as peppermint,methyl salicylate or orange flavoring, and a coloring agent.

When the composition is in the form of a capsule, e.g., a gelatincapsule, it may contain, in addition to materials of the above type, aliquid carrier such as polyethylene glycol or a fatty oil.

The composition may be in the form of a liquid, e.g., an elixir, syrup,solution, aqueous or oily emulsion or suspension, or even dry powderswhich may be reconstituted with water and/or other liquid media prior touse. The liquid may be for oral administration or for delivery byinjection, as two examples. When intended for oral administration,preferred compositions contain, in addition to the present compounds,one or more of a sweetening agent, thickening agent, preservative (e.g.,alkyl p-hydoxybenzoate), dye/colorant and flavor enhancer (flavorant).In a composition intended to be administered by injection, one or moreof a surfactant, preservative (e.g., alkyl p-hydroxybenzoate), wettingagent, dispersing agent, suspending agent (e.g., sorbitol, glucose, orother sugar syrups), buffer, stabilizer and isotonic agent may beincluded. The emulsifying agent may be selected from lecithin orsorbitol monooleate.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid compositions intended for either parenteral or oraladministration should contain an amount of the inventive compound suchthat a suitable dosage will be obtained. Typically, this amount is atleast 0.01% of a compound of the invention in the composition. Whenintended for oral administration, this amount may be varied to bebetween 0.1 and about 70% of the weight of the composition. Preferredoral compositions contain between about 4% and about 50% of the activecycloalkylamine compound. Preferred compositions and preparationsaccording to the present invention are prepared so that a parenteraldosage unit contains between 0.01 to 10% by weight of active compound.

The pharmaceutical composition may be intended for topicaladministration, in which case the carrier may suitably comprise asolution, emulsion, ointment, cream or gel base. The base, for example,may comprise one or more of the following: petrolatum, lanolin,polyethylene glycols, bee wax, mineral oil, diluents such as water andalcohol, and emulsifiers and stabilizers. Thickening agents may bepresent in a pharmaceutical composition for topical administration. Ifintended for transdermal administration, the composition may include atransdermal patch or iontophoresis device. Topical formulations maycontain a concentration of the inventive compound of from about 0.1 toabout 25% w/v (weight per unit volume).

The composition may be intended for rectal administration, in the form,e.g., of a suppository which will melt in the rectum and release thedrug. The composition for rectal administration may contain anoleaginous base as a suitable nonirritating excipient. Such basesinclude, without limitation, lanolin, cocoa butter and polyethyleneglycol. Low-melting waxes are preferred for the preparation of asuppository, where mixtures of fatty acid glycerides and/or cocoa butterare suitable waxes. The waxes may be melted, and the cycloalkylaminecompound is dispersed homogeneously therein by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

The composition may include various materials which modify the physicalform of a solid or liquid dosage unit. For example, the composition mayinclude materials that form a coating shell around the activeingredients. The materials which form the coating shell are typicallyinert, and may be selected from, for example, sugar, shellac, and otherenteric coating agents. Alternatively, the active ingredients may beencased in a gelatin capsule or cachet.

The composition in solid or liquid form may include an agent which bindsto the cycloalkylamine compound and thereby assists in the delivery ofthe active components. Suitable agents which may act in this capacityinclude a monoclonal or polyclonal antibody, a protein or a liposome.

The pharmaceutical composition of the present invention may consist ofgaseous dosage units, e.g., it may be in the form of an aerosol. Theterm aerosol is used to denote a variety of systems ranging from thoseof colloidal nature to systems consisting of pressurized packages.Delivery may be by a liquefied or compressed gas or by a suitable pumpsystem which dispenses the active ingredients. Aerosols of compounds ofthe invention may be delivered in single phase, bi-phasic, or tri-phasicsystems in order to deliver the active ingredient(s). Delivery of theaerosol includes the necessary container, activators, valves,subcontainers, and the like, which together may form a kit. Preferredaerosols may be determined by one skilled in the art, without undueexperimentation.

Whether in solid, liquid or gaseous form, the pharmaceutical compositionof the present invention may contain one or more known pharmacologicalagents used in methods for either modulating ion channel activity in awarm-blooded animal or for modulating ion channel activity in vitro, orused in the treatment of arrhythmia, diseases of the central nervoussystem, convulsion, epileptic spasms, depression, anxiety,schizophrenia, Parkinson's disease, respiratory disorders, cysticfibrosis, asthma, cough, inflammation, arthritis, allergies,gastrointestinal disorders, urinary incontinence, irritable bowelsyndrome, cardiovascular diseases, cerebral or myocardial ischemias,hypertension, long-QT syndrome, stroke, migraine, ophthalmic diseases,diabetes mellitus, myopathies, Becker's myotonia, myasthenia gravis,paramyotonia congentia, malignant hyperthermia, hyperkalemic periodicparalysis, Thomsen's myotonia, autoimmune disorders, graft rejection inorgan transplantation or bone marrow transplantation, heart failure,hypotension, Alzheimer's disease and other mental disorders, andalopecia. Other agents known to cause libido enhancement, localanalgesia or anesthesia may be combined with compounds of the presentinvention.

The pharmaceutical compositions may be prepared by methodology wellknown in the pharmaceutical art. The aminocycloalkyl compounds of theinvention may be in the form of a solvate in a pharmaceuticallyacceptable solvent such as water or physiological saline. Alternatively,the compounds may be in the form of the free base or in the form of apharmaceutically acceptable salt such as the hydrochloride, sulfate,phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate,maleate, lactate, mandelate, salicylate, succinate and other salts knownin the art. The appropriate salt would be chosen to enhancebioavailability or stability of the compound for the appropriate mode ofemployment (e.g., oral or parenteral routes of administration).

A composition intended to be administered by injection can be preparedby combining the cycloalkylamine compound with water, and preferablybuffering agents, so as to form a solution. The water is preferablysterile pyrogen-free water. A surfactant may be added to facilitate theformation of a homogeneous solution or suspension. Surfactants arecompounds that non-covalently interact with the cycloalkylamine compoundso as to facilitate dissolution or homogeneous suspension of thecycloalkylamine compound in the aqueous delivery system. Surfactants aredesirably present in aqueous compositions of the invention because thecycloalkylamine compounds of the present invention are typicallyhydrophobic. Other carriers for injection include, without limitation,sterile peroxide-free ethyl oleate, dehydrated alcohols, propyleneglycol, as well as mixtures thereof.

Suitable pharmaceutical adjuvants for the injecting solutions includestabilising agents, solubilising agents, buffers, and viscosityregulators. Examples of these adjuvants include ethanol,ethylenediaminetetraacetic acid (EDTA), tartrate buffers, citratebuffers, and high molecular weight polyethylene oxide viscosityregulators. These pharmaceutical formulations may be injectedintramuscularly, epidurally, intraperitoneally, or intravenously.

Pharmacological Testing

As noted above, the present invention provides for utilising thecompounds described above in in vitro and in vivo methods. In oneembodiment, ion channels, such as cardiac sodium channels, are blockedin vitro or in vivo.

Ion channels are ubiquitous membrane proteins in the cells ofwarm-blooded animals such as mammals. Their critical physiological rolesinclude control of the electrical potential across the membrane,mediation of ionic and fluid balance, facilitation of neuromuscular andneuronal transmission, rapid transmembrane signal transduction, andregulation of secretion and contractility.

Accordingly, compounds that are capable of modulating the activity orfunction of the appropriate ion channels will be useful in treating orpreventing a variety of diseases or disorders caused by defective orinadequate function of the ion channels. The compounds of the inventionare found to have significant activity in modulating ion channelactivity both in vivo and in vitro.

Thus, the present invention provides for methods of treating a diseaseor condition in a warm-blooded animal suffering from or having thedisease or condition, and/or preventing a disease or condition fromarising in a warm-blooded animal, wherein a therapeutically effectiveamount of a compound of formula (I), or a composition containing acompound of formula (I) is administered to a warm-blooded animal in needthereof. The diseases and conditions to which the compounds,compositions and methods of the present invention may be applied are asfollows: arrhythmia, diseases of the central nervous system, convulsion,epileptic spasms, depression, anxiety, schizophrenia, Parkinson'sdisease, respiratory disorders, cystic fibrosis, asthma, cough,inflammation, arthritis, allergies, gastrointestinal disorders, urinaryincontinence, irritable bowel syndrome, cardiovascular diseases,cerebral or myocardial ischemias, hypertension, long-QT syndrome,stroke, migraine, ophthalmic diseases, diabetes mellitus, myopathies,Becker's myotonia, myasthenia gravis, paramyotonia congentia, malignanthyperthermia, hyperkalemic periodic paralysis, Thomsen's myotonia,autoimmune disorders, graft rejection in organ transplantation or bonemarrow transplantation, heart failure, hypotension, Alzheimer's diseaseor other mental disorder, and alopecia.

Furthermore, the present invention provides a method for producing localanalgesia or anesthesia in a warm-blooded animal which includesadministering to a warm-blooded animal in need thereof an effectiveamount of a compound of formula (I) or a pharmaceutical compositioncontaining a compound of formula (I). These methods may be used torelieve or forestall the sensation of pain in a warm-blooded animal.

Furthermore, the present invention provides a method wherein apreparation that contains ion channels is exposed to, or a warm-bloodedanimal (e.g., a mammal, such as a human) is administered an effectiveamount of an aminocycloalkyl ether compound of the invention. Suitablepreparations containing cardiac sodium channels include cells isolatedfrom cardiac tissue as well as cultured cell lines. Treatment of such apreparation would entail, for example, incubation of the ion channelswith a compound under conditions and for a time sufficient to permitmodulation of the activity of the channels by the compound.

In another embodiment, the compounds described above are provided fortreating arrhythmia. As used herein, “treating arrhythmia” refers toboth therapy for arrhythmia and for the prevention of arrhythmiasoccurring in a heart that is susceptible to arrhythmia. An effectiveamount of a composition of the present invention is used to treatarrhythmia in a warm-blooded animal, such as a human. Methods ofadministering effective amounts of antiarrhythmic agents are well knownin the art and include the administration of an oral or parenteraldosage form. Such dosage forms include but are not limited to,parenteral dosage form. Such dosage forms include, but are not limitedto, parenteral solutions, tablets, capsules, sustained release implants,and transdermal delivery systems. Generally, oral or intravenousadministration is preferred. The dosage amount and frequency areselected to attain effective levels of the agent without harmfuleffects. It will generally range from a dosage of from about 0.1 toabout 100 mg/kg/day, and typically from about 0.1 to 10 mg/kg whereadministered orally or intravenously for antiarrhythmic effect.

Administration of compositions of the present invention may be carriedout in combination with the administration of other agents. For example,it may be desired to administer an opioid antagonist, such as naloxone,if a compound exhibits opioid activity where such activity may not bedesired. The naloxone may antagonize opioid activity of the administeredcompound without adverse interference with the antiarrhythmic activity.As another example, an aminocycloalkyl ether compound of the inventionmay be co-administered with epinephrine in order to include localanesthesia.

In order to assess whether a compound of the present invention has adesired pharmacological activity, it is subjected to a series of tests.The precise test to employ will depend on the physiological response ofinterest. The published literature contains numerous protocols fortesting the efficacy of a potential therapeutic agent, and theseprotocols may be employed with the present compounds and compositions.

For example, in connection with treatment or prevention of arrhythmia, aseries of four tests may be conducted. In the first of these tests, acompound of the present invention is given as increasing (doubling witheach dose) intravenous boluses every 8 minutes to a pentobarbitalanesthetized rat. The effects of the compound on blood pressure, heartrate and the ECG are measured at 30 seconds, 1, 2, 4 and 8 minutes aftereach dose. Increasing doses are given until the animal dies. The causeof death is identified as being of either respiratory or cardiac origin.This test gives an indication as to whether the compound is modulatingthe activity of sodium channels and/or potassium channels, and inaddition gives information about acute toxicity. The indices of sodiumchannel blockade are increasing P-R interval and QRS widening of theECG. Potassium channel blockade results in Q-T interval prolongation ofthe ECG.

A second test involves administration of a compound as an infusion topentobarbital anesthetized rats in which the left ventricle is subjectedto electrical square wave stimulation performed according to a presetprotocol described in further detail below. This protocol includes thedetermination of thresholds for induction of extrasystoles andventricular fibrillation. In addition, effects on electricalrefractoriness are assessed by a single extra beat technique. Inaddition effects on blood pressure, heart rate and the ECG are recorded.In this test, sodium channel blockers produce the ECG changes expectedfrom the first test. In addition, sodium channel blockers also raise thethresholds for induction of extrasystoles and ventricular fibrillation.Potassium channel blockade is revealed by increasing refractoriness andwidening of the Q-T intervals of the ECG.

A third test involves exposing isolated rat hearts to increasingconcentrations of a compound. Ventricular pressures, heart rate,conduction velocity and ECG are recorded in the isolated heart in thepresence of varying concentrations of the compound. The test providesevidence for direct toxic effects on the myocardium. Additionally,selectivity, potency and efficacy of action of a compound can beascertained under conditions simulating ischemia. Concentrations foundto be effective in this test are expected to be efficacious in theelectrophysiological studies.

A fourth test is estimation of the antiarrhythmic activity of a compoundagainst the arrhythmias induced by coronary artery occlusion inanaesthetized rats. It is expected that a good antiarrhythmic compoundwill have antiarrhythmic activity at doses which have minimal effects oneither the ECG, blood pressure or heart rate under normal conditions andpreferably on all these parameters.

All of the foregoing tests are performed using rat tissue. In order toensure that a compound is not having effects which are only specific torat tissue, further experiments are performed in dogs and primates. Inorder to assess possible sodium channel and potassium channel blockingaction in vivo in dogs, a compound is tested for effects on the ECG,ventricular epicardial conduction velocity and responses to electricalstimulation. An anesthetized dog is subjected to an open chest procedureto expose the left ventricular epicardium. After the pericardium isremoved from the heart a recording/stimulation electrode is sewn ontothe epicardial surface of the left ventricle. Using this array, andsuitable stimulation protocols, conduction velocity across theepicardium as well as responsiveness to electrical stimulation can beassessed. This information coupled with measurements of the ECG allowsone to assess whether sodium and/or potassium channel blockade occurs.As in the first test in rats, a compound is given as a series ofincreasing bolus doses. At the same time possible toxic effects of acompound on the dog's cardiovascular system are assessed.

The effects of a compound on the ECG and responses to electricalstimulation are also assessed in intact, halothane anesthetized baboons(Papio anubis). In this preparation, a blood pressure cannula and ECGelectrodes arc suitably placed in an anesthetized baboon. In addition, astimulating electrode is placed into the right ventricle, together witha monophasic action potential electrode. As in the tests describedabove, ECG and electrical stimulation response to a compound reveal thepossible presence of sodium and/or potassium channel blockade. Themonophasic action potential also reveals whether a compound widens theaction potential, an action expected of a potassium channel blocker.

As another example, in connection with the mitigation or prevention ofthe sensation of pain, the following test may be performed. To determinethe effects of a compound of the present invention on an animal'sresponse to a sharp pain sensation, the effects of a slight prick from a7.5 g weighted syringe fitted with a 23 G needle applied to the shavedback of a guinea pig (Cavia porcellus) is assessed followingsubcutaneous administration of a solution of the compound in saline(e.g., 50 μl, 10 mg/ml) to raise a visible bleb on the skin. Each testis performed on the central area of the bleb and also on its peripheryto ascertain the diffusion of the test solution from the point ofadministration. If the test animal produces a flinch in response to thestimulus, this demonstrates the absence of blockade of pain sensation.Testing is performed at intervals for up to 4 hours post administration.The sites of bleb formation are examined after 24 hours and showed noskin abnormalities arise from the local administration of testsubstances or the vehicle used in the preparation of the test solutions.

Other Compositions

The present invention also provides kits that contain a pharmaceuticalcomposition which includes one or more compounds of the above formulae.The kit also includes instructions for the use of the pharmaceuticalcomposition for modulating the activity of ion channels, for thetreatment of arrhythmia or for the production of local analgesia and/oranesthesia, and for the other utilities disclosed herein. Preferably, acommercial package will contain one or more unit doses of thepharmaceutical composition. For example, such a unit dose may be anamount sufficient for the preparation of an intravenous injection. Itwill be evident to those of ordinary skill in the art that compoundswhich are light and/or air sensitive may require special packagingand/or formulation. For example, packaging may be used which is opaqueto light, and/or sealed from contact with ambient air, and/or formulatedwith suitable coatings or excipients.

The following examples are offered by way of illustration and not by wayof limitation. In the Examples, and unless otherwise specified, startingmaterials were obtained from well-known commercial supply houses, e.g.,Aldrich Chemical Company (Milwaukee, Wis.), and were of standard gradeand purity. “Ether” and “ethyl ether” both refer to diethyl ether: “h.”refers to hours; “min.” refers to minutes: “GC” refers to gaschromatography: “v/v” refers to volume per volume; and ratios are weightratios unless otherwise indicated.

EXAMPLES Example 1(1R,2R)/(1S,2S)-2-(4-MORPHOLINYL)-1-(2-NAPHTHALENETHOXY)CYCLOPENTANEMONOHYDROCHLORIDE (COMPOUND #1)

The following reaction sequence is illustrated in FIG. 1.

i) (1R,2R)/(1S,2S)-2-(4-Morpholinyl)cyclopentanol: A mixture ofmorpholine (15.0 ml, 172 mmol) and cyclopentene oxide (15 ml, 172 mmol)in water (5 ml) was refluxed for 3 hours. The cooled reaction mixturewas then partitioned between 40% NaOH aqueous solution (100 ml) anddiethyl ether (100 ml). The aqueous layer was extracted twice more withdiethyl ether (2×50 ml). The combined organic layers were dried oversodium sulfate and the solvent was evaporated in vacuo. Vacuumdistillation provided 20.6 g of the title compound.

ii) (1R,2R)/(1S,2S)-2-(4-Morpholinyl)-1-(2-naphthalenethoxy)cyclopentanemonohydrochloride: To a chilled (0° C.) solution of(1R,2R)/(1S,2S)-2-(4-morpholinyl)cyclopentanol (2.77 g, 16.20 mmol) andtriethylamine (3.4 ml, 24.00 mmol) in dichloromethane (50 ml) was addedvia cannula a solution of methanesulfonyl chloride (1.55 ml, 20.00 mmol)in dichloromethane (50 ml). The reaction mixture was stirred for anotherhour at 0° C. and then at room temperature for 4 hours. The reactionmixture was washed with water (2×50 ml) and the combined aqueouswashings back-extracted with dichloromethane (50 ml). The combinedorganic layers were dried over sodium sulfate and concentrated in vacuoto provide 4.0 g of the crude mesylate.

iii) Sodium hydride, 80% oil dispersion (0.60 g, 25.00 mmol), was washedwith hexanes (3×10 ml), and then suspended in anhydrousdimethylformamide (50 ml). To this suspension was added via cannula asolution of 2-naphthalenecthanol (3.4 g, 20.00 mmol) in anhydrousdimethylformamide (50 ml). The reaction mixture was stirred at roomtemperature for one hour.

iv) The mesylate dissolved in dimethylformamide (50 ml) was addedquickly to the alkoxide mixture (iii). The reaction mixture was heatedat 85° C. for 2 hours, and then at 45° C. overnight. The reactionmixture was poured into iced water (800 ml) and extracted with ethylacetate (3×200 ml). The combined organic extracts were back-washed witha saturated aqueous sodium chloride solution (300 ml) and dried oversodium sulfate. Evaporation of the solvent in vacuo provided 6.7 g ofoil, which was dissolved in 1M HCl aqueous solution (50 ml) and water(150 ml). The acidic aqueous solution was extracted with diethyl ether(2×100 ml) and then adjusted to pH 10 with 50% aqueous sodium hydroxidesolution. The basic aqueous solution was extracted with ethyl ether(2×100 ml) and the combined organic layers were dried over sodiumsulfate and concentrated in vacuo to give 1.47 g of the crude freeaminoether. The crude product was purified by chromatography columnusing silica gel 60, (230–400 mesh, BDH Inc.) and a mixture of 3%methanol in dichloromethane as eluent. The purified product wasdissolved in diethyl ether (50 ml) and converted to themonohydrochloride salt by the addition of ethereal HCl (50 ml). Thesolvent was evaporated in vacuo; the residue dissolved in the minimumamount of warm absolute ethanol and diethyl ether was added in order totrigger crystallisation. The crystals were collected yielding 0.29 g ofthe title compound.

Compound number 1 has a calculated molecular weight of 361.91, andprovided elemental analysis as set forth in Table 1.

Example 2(1R,2R)/(1S,2S)-2-(3-KETOPYRROLIDINYL)-1-(2,6-DICHLOROPHENETHOXY)CYCLOPENTANEMONOHYDROCHLORIDE (COMPOUND #2)

The following reaction sequences are illustrated in FIGS. 2A and 2B.

i) N-Benzyloxycarbonyl-3-pyrrolidinol: To a chilled (−60° C.), stirredsolution of (R)-(+)-3-pyrrolidinol (20.0 g, 98%, 224.9 mmol) andtriethylamine (79.2 ml, 99%, 562 mmol) in dichloromethane (200 ml) wasadded dropwise over 45 min., a solution of benzyl chloroformate (33.8ml, 95%, 224.9 mmol) in dichloromethane (80 ml). The reaction mixture (ayellow suspension) was allowed to warm up to room temperature and wasstirred under argon at room temperature overnight. The reaction mixturewas then quenched with 1M aqueous HCl solution (350 ml) and the organiclayer was collected. The acidic aqueous layer was extracted withdichloromethane (2×150 ml) and the combined organic layers were driedover sodium sulfate. Evaporation in vacuo of the solvent provided 59.62g of pale yellow oil, which was subjected to high vacuum for 15 min. toyield 58.23 g (17% over theoretical yield) of the crude title compoundwhich was suitable for use in the next step without any furtherpurification.

ii) N-Benzyloxycarbonyl-3-pyrrolidinone: To a chilled (−60° C.), stirredsolution of oxalyl chloride (23 ml, 98%, 258.6 mmol) in dichloromethane(400 ml) was added dropwise a solution of anhydrous dimethyl sulfoxide(36.7 ml, 517.3 mmol) in dichloromethane (20 ml) at a rate that thetemperature remained below −40° C. The reaction mixture was then stirredat −60° C. for 15 min. Then a solution ofN-benzyloxycarbonyl-3-pyrrolidinol (58.22 g, no more than 224.9 mmol) indichloromethane (80 ml) was added dropwise, keeping the reaction mixturetemperature below −50° C. The reaction mixture was then stirred at −60°C. for 30 min. before triethylamine (158.3 ml, 99%, 1.125 mol) wasadded. The resultant mixture was allowed to warm up to room temperatureand then washed successively with water (600 ml), 1M aqueous HClsolution (580 ml) and water (400 ml). The organic layer was dried oversodium sulfate and concentrated in vacuo to give 54.5 g of amber oil,which was stirred under high vacuum at room temperature for 25 min. togive 52.08 g of the crude title compound which was suitable for use inthe next step without further purification.

iii) 7-Benzyloxycarbonyl-1,4-dioxa-7-azaspiro [4,4]nonane: A mixture ofN-benzyloxycarbonyl-3-pyrrolidinone (51.98 g. 224.9 mmol), ethyleneglycol (18.8 ml, 99+%, 337.4 mmol) and p-toluenesulfonic acidmonohydrate (1.04 g, 5.4 mmol) in toluene (180 ml) was refluxed in aDean & Stark apparatus for 16 hours. The reaction mixture was thendiluted with more toluene (250 ml) and washed with saturated aqueoussodium bicarbonate solution (150 ml) and saturated aqueous sodiumchloride solution (2×150 ml). The combined aqueous layers wereback-extracted with toluene (100 ml). The combined organic layers weredried over sodium sulfate and concentrated in vacuo to give 79.6 g ofdark oil. A solution of the crude product in ethanol (500 ml) wasdecolorized by elution through a bed of activated carbon (80 g). Thecharcoal was washed with more ethanol (1000 ml) and toluene (500 ml).The filtrate was concentrated in vacuo and subjected to high vacuum for1 hour to yield 63.25 g of the crude title compound which was suitablefor the next step without any further purification.

iv) 1,4-Dioxa-7-aspiro[4.4]nonane: A mixture of7-benzyloxycarbonyl-1,4-dioxa-7-azaspiro[4,4]nonane (34.79 g. no morethan 123.7 mmol) and 10% Pd-C (13.9 g) in ethanol (90 ml) was agitatedunder hydrogen (60 psi) in a Parr apparatus at room temperature for 1.5hour. The catalyst was filtered off, the solvent was evaporated in vacuoand the residue was subjected to high vacuum for 20 min. to yield 15.86g of the title compound (yield 99.3%).

v) (1R,2R)/(1S,2S)-2-(1,4-Dioxa-7-azaspiro[4,4]non-7-yl)cyclopentanol: Amixture of 1,4-dioxa-7-azaspiro[4,4]nonane (5.17 g, 40 mmol),cyclopentene oxide (8.54 ml, 96 mmol) and water (1.7 ml) was heated at80° C. for 2 hours. The reaction mixture was then partitioned between40% aqueous sodium hydroxide solution (15 ml) and diethyl ether (30 ml).The basic aqueous layer was extracted twice more with diethyl ether(2×30 ml). The combined organic extracts were dried over sodium sulfateand concentrated in vacuo. The residue was stirred under high vacuum at50° C. for 1 hour (to remove the excess of cyclopentene oxide) to yield7.13 g of the crude title compound (yield 83.5%).

vi)(1R,2R)/(1S,2S)-2-[1,4-Dioxa-7-azaspiro[4,4]non-7-yl]-1-(2,6-dichlorophenethoxy)cyclopentane:To a chilled (0° C.), stirred solution of(1R,2R)/(1S,2S)-2-(1,4-Dioxa-7-azaspiro[4,4]non-7-yl)cyclopentanol (1.88g, 8.8 mmol) and triethylamine (1.16 g, 11.44 mmol) in dichloromethane(240 ml) was added dropwise methanesulfonyl chloride (0.9 ml, 11.44mmol). The reaction mixture was stirred at 0° C. for 45 min. and then atroom temperature for 3 hours. The reaction mixture was then washed witha mixture (1:1, v/v. 12 ml) of water and saturated aqueous sodiumbicarbonate solution. The aqueous layer was back-extracted withdichloromethane (10 ml). The combined organic extracts were dried oversodium sulfate, the solvent was evaporated in vacuo and the residue wassubjected to high vacuum for 4 hours to yield the crude mesylatesuitable for the next step without any further purification.

vii) To sodium hydride (323 mg, 10.56 mmol) suspended in anhydrous(freshly distilled from sodium) ethylene glycol dimethyl ether (20 ml)was added a solution of 2,6-dichlorophenethanol (2.01 g, 10.56 mmol) inanhydrous* ethylene glycol dimethyl ether (10 ml). The resultant mixturewas then stirred at room temperature for 3 hours.

viii) A solution of mesylate (vi) in anhydrous* ethylene glycol dimethylether (10 ml) was added quickly to the alkoxide (vii) and the resultingmixture was readily heated to reflux under argon for 16 hours. Theorganic solvent was evaporated in vacuo and to the residue was addedwater (50 ml). The aqueous solution was acidified with 10% HCl aqueoussolution to pH 0.5. The acidic aqueous layer was extracted with diethylether (2×30 ml) in order to extract unreacted 2,6-dichlorophenethanol.The pH of the aqueous solution was adjusted to pH 5.0 with 5M NaOHaqueous solution and then extracted with diethyl ether (2×50 ml). Thecombined organic extracts were dried over sodium sulfate and the solventwas evaporated in vacuo to yield 2.2 g of the title compound which wassuitable for the next step without any further purification.

ix)(1R,2R/(1S,2S)-2-(3-Ketopyrrolidinyl)-1-(2,6-dichlorophenethoxy)cyclopentanemonohydrochloride: A solution of(1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4,4]non-7-yl]-1-(2,6-dichlorophenethoxy)cyclohexane(2.2 g) with 6M HCl aqueous solution (20 ml) in 2-butanone (80 ml) wasrefluxed for 12 hours. The butanone was evaporated in vacuo and theresidual aqueous solution was diluted with water (100 ml). The aqueoussolution was extracted with diethyl ether (2×50 ml) and then withdichloromethane (3×50 ml). The pooled dichloromethane extracts weredried over sodium sulfate and the solvent was evaporated in vacuo. Theresidual oil was azeotropically dried with toluene. The resulting stickyproduct was vigorously stirred overnight in diethyl ether (150 ml) withoccasional scratching to trigger crystallisation of the title compound(1.9 g, 57%).

Compound number two had a calculated molecular weight of 378.73, andprovided the elemental analysis data set forth in Table 1.

TABLE 1 Compound Formula Calculated Found #1 C₂₁H₂₈NO₂Cl C 69.69, H7.80, C 69.23, H 7.71, N 3.87% N 3.83% #2 C₁₇H₂₂NO₂Cl₃ C 53.91, H 5.86,C 54.13, H 5.68, N 3.70% N 3.58%

Example 3 ASSESSMENT OF ANTIARRHYTHMIC EFFICACY

Antiarrhythmic efficacy was assessed by investigating the effect of acompound on the incidence of cardiac arrhythmias in conscious ratssubjected to coronary artery occlusion. Rats weighing 200–300 gms weresubjected to preparative surgery and assigned to groups in a randomblock design. In each case, the animal was anesthetized with halothaneduring surgical preparation. The left femoral artery was cannulated formeasurement of mean arterial blood pressure and withdrawal of bloodsamples. The left femoral vein was also cannulated for injection ofdrugs. The thoracic cavity was opened and a polyethylene occluderloosely placed around the left anterior descending coronary artery. Thethoracic cavity was then closed. ECG was recorded by insertion ofelectrodes placed along the anatomical axis of the heart. All cannulaeand electrode leads were exteriorized in the mid scapular region. In arandom and double-blind manner, about 0.5 to 2 hours post-surgery, aninfusion of vehicle, or the compound to be tested was given. After 5–15minutes infusion, the occluder was pulled so as to produce coronaryartery occlusion. ECG, arrhythmias, blood pressure, heart rate andmortality were monitored for 30 minutes after occlusion. Arrhythmiaswere recorded as ventricular tachycardia (VT) and ventricularfibrillation (VF) and scored according to Curtis, M. J. and Walker, M.J. A., Cardiovasc. Res. 22:656 (1988) (see Table 2).

TABLE 2 Score Description 0 0–49 VPBs 1 50–499 VPBs 2 >499 VPBs and/or 1episode of spontaneously reverting VT or VF 3 >1 episode of VT or VF orboth (>60 s total combined duration) 4 VT or VF or both (60–119 s totalcombined duration) 5 VT or VF or both (>119 s total combined duration) 6fatal VF starting at >15 min after occlusion 7 fatal VF starting atbetween 4 min and 14 min 59 s after occlusion 8 fatal VF starting atbetween 1 min and 3 min 59 s after occlusion 9 fatal VF starting <1 minafter occlusion Where: VPB = ventricular premature beats VT =ventricular tachycardia VF = ventricular fibrillation

Rats were excluded from the study if they did not exhibit pre-occlusionserum potassium concentrations within the range of 2.9–3.9 mM. Occlusionis associated with increases in R-wave height and “S-T” segmentelevation: and an occluded zone (measured after death by cardiogreen dyeperfusion) in the range of 25%–50% of total left-ventricular weight.

Table 3 describes the result of tests of the compounds described thereinas values of a given infusion rate in micromol/kg/min. (ED₅₀AA) whichwill reduce the arrhythmia score in treated animals to 50% of that shownby animals treated only with the vehicle in which the test drug(s) isdissolved.

TABLE 3 Compound ED₅₀AA #1 1.5 #2 4

Example 4 MEASUREMENT OF ECG PARAMETERS

Rats weighing 200–250 gms were used in this example. Animals wereanesthetized with 60 mg/kg pentobarbital i.p. The carotid artery andjugular vein were cannulated for measurement of blood pressure and druginjection, respectively. ECG was recorded by insertion of electrodesplaced along the anatomical axis of the heart. All compounds were givenas bolus injections.

Various ECG parameters were measured. Table 4 describes the results ofthe tests as ED₂₅ (micromol/kg) which are the doses required to producea 25% increase in the parameter measured (NE=not estimated). Theincreases in P—R interval and QRS interval indicate cardiac sodiumchannel blockage while the increase in Q-T interval indicates ancillarycardiac potassium channel blockage which is the property of a type 1aantiarrhythmic.

TABLE 4 Compound PR QRS QT #1 45 37 2.5 #2 NE 9 3.3 NE = Not Estimated

Example 5 ASSESSMENT OF SODIUM CHANNEL BLOCKAGE

Rats were prepared according to the preceding procedure. Two silverstimulating electrodes were inserted through the chest wall andimplanted in the left ventricle. Square wave stimulation was used todetermine threshold current for capture, ventricular fibrillationthreshold current, and effective refractory period (Howard, P. G. andWalker, M. J. A., Proc. West. Pharmacol. Soc. 33:123–127 (1990)). Table5 contains ED₂₅ values for these indices of cardiac sodium channelblockage, where the ED₂₅ is the infusion rate in micromol/kg/minute ofcompound required to elicit a 25% increase from control. The increasesin refractoriness indicate ancillary blockage of potassium channels. Thethreshold current for capture is represented by “It”. The fibrillationthreshold current is represented by “VFT”. The effective refractingperiod is represented by “ERP”.

TABLE 5 Compound It VFT ERP #1 3.3 1.3 2.5 #2 10 NE 2.6 NE = NotEstimated

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually incorporated by reference.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1. A composition comprising a compound of formula (I), or a solvate orpharmaceutically acceptable salt thereof:

wherein, independently at each occurrence, n is selected from 1, 3 and4; Q is either O (oxygen) or —O—C(O)—; X is selected from a direct bond,—C(R₆,R₁₄)—Y—, and —C(R₁₃)═CH—; Y is selected from a direct bond, O, S,and C₁–C₄alkylene; R₁₃ is selected from hydrogen, C₁–C₆alkyl,C₃–C₈cycloalkyl, aryl, and benzyl; R₁ and R₂ are independently selectedfrom C₃–C₈alkoxyalkyl, C₁–C₈hydroxyalkyl, and C₇–C₁₂aralkyl; or R₁ andR₂, are taken together with the nitrogen atom to which they are directlyattached in formula (I), to form a ring denoted by formula (II):

wherein the ring of formula (II) is formed from the nitrogen as shown aswell as three to nine additional ring atoms independently selected fromcarbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atomsmay be joined together by single or double bonds, and where any one ormore of the additional carbon ring atoms may be substituted with one ortwo substituents selected from hydrogen, hydroxy, C₁–C₃hydroxyalkyl,oxo, C₂–C₄acyl, C₁–C₃alkyl, C₂–C₄alkylcarboxy, C₁–C₃alkoxy,C₁–C₂₀alkanoyloxy, or may be substituted to form a spiro five- orsix-membered heterocyclic ring containing one or two heteroatomsselected from oxygen and sulfur; and any two adjacent additional carbonring atoms may be fused to a C₃–C₈carbocyclic ring, and any one or moreof the additional nitrogen ring atoms may be substituted withsubstituents selected from hydrogen, C₁–C₆alkyl, C₂–C₄acyl,C₂–C₄hydroxyalkyl and C₃–C₈alkoxyalkyl; or R₁ and R₂, are taken togetherwith the nitrogen atom to which they are directly attached in formula(I), to form a bicyclic ring system selected from3-azabicyclo[3.2.2]nonan-3-yl, 2-aza-bicyclo[2.2.2]octan-2-yl,3-azabicyclo[3.1.0]-hexan-3-yl, and 3-azabicyclo[3.2.0]-heptan-3-yl; R₃and R₄ are independently attached to the cycloalkyl ring shown informula (I) at other than the 1 and 2 positions and are independentlyselected from hydrogen, hydroxy, C₁–C₆alkyl, and C₁–C₆alkoxy, and, whenboth R₃ and R₄ are attached to the same cycloalkane ring atom, maytogether form a spiro five- or six-membered heterocyclic ring containingone or two heteroatoms selected from oxygen and sulfur; R₅, R₆ and R₁₄are independently selected from hydrogen, C₁–C₆alkyl, aryl and benzyl,or R₆ and R₁₄, when taken together with the carbon to which they areattached, may form a spiro C₃–C₅cycloalkyl; A is selected fromC₅–C₁₂alkyl, a C₃–C₁₃carbocyclic ring, and ring systems selected fromformulae (III), (IV), (V), (VI), (VII) and (VIII):

where R₇, R₈ and R₉ are independently selected from bromine, chlorine,fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,nitro, sulfamyl, trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl,C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, aryl and N(R₁₅,R₁₆)where R₁₅ and R₁₆ are independently selected from hydrogen, acetyl,methanesulfonyl, and C₁–C₆alkyl;

and

where R₁₀ and R₁₁ are independently selected from bromine, chlorine,fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,nitro, sulfamyl, trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl,C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, and N(R₁₅,R₁₆) whereR₁₅ and R₁₆ are independently selected from hydrogen, acetyl,methanesulfonyl, and C₁–C₆alkyl;

where R₁₂ is selected from bromine, chlorine, fluorine, carboxy,hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl,trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl, C₁–C₆alkoxy,C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, and N(R₁₅,R₁₆) where R₁₅ and R₁₆are independently selected from hydrogen, acetyl, methanesulfonyl, andC₁–C₆alkyl; and Z is selected from CH, CH₂, O, N and S, where Z may bedirectly bonded to “X” as shown in formula (I) when Z is CH or N, or Zmay be directly bonded to R₁₇ when Z is N, and R₁₇ is selected fromhydrogen, C₁–C₆alkyl, C₃–C₈cycloalkyl, aryl and benzyl;

including isolated enantiomeric, diastereomeric and geometric isomersthereof, and mixtures thereof.
 2. A composition comprising a compoundselected from the group consisting of(1R,2R)-2-(4-Morpholinyl)-1-(2-naphthalenethoxy)cyclopentane;(1S,2S)-2-(4-Morpholinyl)-1-(2-naphthalenethoxy)cyclopentane;(1R,2R)-2-(3-Ketopyrrolidinyl)-1-(2,6-dichlorophenethoxy)cyclopentane;(1S,2S)-2-(3-Ketopyrrolidinyl)-1-(2,6-dichlorophenethoxy)cyclopentane;and pharmaceutically acceptable salts and solvates of any of theforegoing; or a mixture of compounds selected from the group consistingof a mixture of(1R,2R)-2-(4-Morpholinyl)-1-(2-naphthalenethoxy)cyclopentane and(1S,2S)-2-(4-Morpholinyl)-1-(2-naphthalenethoxy)cyclopentane, a mixtureof (1R,2R)-2-(3-Ketopyrrolidinyl)-1-(2,6-dichlorophenethoxy)cyclopentaneand(1S,2S)-2-(3-Ketopyrrolidinyl)-1-(2,6-dichlorophenethoxy)cyclopentane;and a mixture of pharmaceutically acceptable salts and solvates of anyof the foregoing.
 3. The composition of claim 1, wherein R₁ and R₂, aretaken together with the nitrogen atom to which they are directlyattached in formula (I), to form a ring denoted by formula (II):

wherein the ring of formula (II) is formed from the nitrogen as shown aswell as three to nine additional ring atoms independently selected fromcarbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atomsmay be joined together by single or double bonds, and where any one ormore of the additional carbon ring atoms may be substituted with one ortwo substituents selected from hydrogen, hydroxy, C₁–C₃hydroxyalkyl,oxo, C₂–C₄acyl, C₁–C₃alkyl, C₂–C₄alkylcarboxy, C₁–C₃alkoxy,C₁–C₂₀alkanoyloxy, or may be substituted to form a spiro five- orsix-membered heterocyclic ring containing one or two heteroatomsselected from oxygen and sulfur; and any two adjacent additional carbonring atoms may be fused to a C₃–C₈carbocyclic ring, and any one or moreof the additional nitrogen ring atoms may be substituted withsubstituents selected from hydrogen, C₁–C₆alkyl, C₂–C₄acyl,C₂–C₄hydroxyalkyl and C₃–C₈alkoxyalkyl; or R₁ and R₂, are taken togetherwith the nitrogen atom to which they are directly attached in formula(I), to form a bicyclic ring system selected from3-azabicyclo[3.2.2]nonan-3-yl, 2-aza-bicyclo[2.2.2]octan-2-yl,3-azabicyclo[3.1.0]-hexan-3-yl, and 3-azabicyclo[3.2.0]-heptan-3-yl. 4.A method for treating arrhythmia in a warm-blooded animal comprisingadministering to a warm-blooded animal in need of such treatment atherapeutically effective amount of a composition according to claim 1or 3 or a composition or mixture of compounds according to claim
 2. 5. Amethod for modulating ion channel activity in a warm-blooded animalcomprising administering to a warm-blooded animal in need of ion channelactivity modulation a therapeutically effective amount of a compositionaccording to claim 1 or 3 or a composition or mixture of compoundsaccording to claim
 2. 6. A method for modulating ion channel activity invitro comprising contacting an in vitro ion channel with a compositionaccording to claim 1 or 3 or a composition or mixture of compoundsaccording to claim
 2. 7. A pharmaceutical composition comprising anamount of a composition according to claim 1 or 3 or a composition ormixture of compounds according to claim 2 effective to treat diseases ofthe central nervous system in a warm-blooded animal in need of thetreatment, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 8. A method for treating diseases of the central nervoussystem in a warm-blooded animal comprising administering to awarm-blooded animal in need thereof a therapeutically effective amountof a composition according to claim 1 or 3 or a composition or mixtureof compounds according to claim
 2. 9. A pharmaceutical compositioncomprising an amount of a composition according to claim 1 or 3 or acomposition or mixture of compounds according to claim 2 effective totreat convulsion in a warm-blooded animal in need of the treatment, anda pharmaceutically acceptable carrier, diluent, or excipient.
 10. Amethod for treating convulsion in a warm-blooded animal comprisingadministering to a warm-blooded animal in need thereof a therapeuticallyeffective amount of a composition according to claim 1 or 3 or acomposition or mixture of compounds according to claim
 2. 11. Apharmaceutical composition comprising an amount of a compositionaccording to claim 1 or 3 or a composition or mixture of compoundsaccording to claim 2 effective to treat epileptic spasms in awarm-blooded animal in need of the treatment, and a pharmaceuticallyacceptable carrier, diluent, or excipient.
 12. A method for treatingepileptic spasms in a warm-blooded animal comprising administering to awarm-blooded animal in need thereof a therapeutically effective amountof a composition according to claim 1 or 3 or a composition or mixtureof compounds according to claim
 2. 13. A pharmaceutical compositioncomprising an amount of a composition according to claim 1 or 3 or acomposition or mixture of compounds according to claim 2 effective totreat depression, anxiety or schizophrenia, in a warm-blooded animal inneed of the treatment, and a pharmaceutically acceptable carrier,diluent, or excipient.
 14. A method for treating depression, anxiety orschizophrenia, in a warm-blooded animal comprising administering to awarm-blooded animal in need thereof a therapeutically effective amountof a composition according to claim 1 or 3 or a composition or mixtureof compounds according to claim
 2. 15. A pharmaceutical compositioncomprising an amount of a composition according to claim 1 or 3 or acomposition or mixture of compounds according to claim 2 effective totreat Parkinson's disease in a warm-blooded animal in need of thetreatment, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 16. A method for treating Parkinson's disease in awarm-blooded animal comprising administering to a warm-blooded animal inneed thereof a therapeutically effective amount of a compositionaccording to claim 1 or 3 or a composition or mixture of compoundsaccording to claim
 2. 17. A pharmaceutical composition comprising anamount of a composition according to claim 1 or 3 or a composition ormixture of compounds according to claim 2 effective to treat respiratorydisorders in a warm-blooded animal in need of the treatment, and apharmaceutically acceptable carrier, diluent, or excipient.
 18. A methodfor treating respiratory disorders in a warm-blooded animal comprisingadministering to a warm-blooded animal in need thereof a therapeuticallyeffective amount of a composition according to claim 1 or 3 or acomposition or mixture of compounds according to claim
 2. 19. Apharmaceutical composition comprising an amount of a compositionaccording to claim 1 or 3 or a composition or mixture of compoundsaccording to claim 2 effective to treat cystic fibrosis in awarm-blooded animal in need of the treatment, and a pharmaceuticallyacceptable carrier, diluent, or excipient.
 20. A method for treatingcystic fibrosis in a warm-blooded animal comprising administering to awarm-blooded animal in need thereof a therapeutically effective amountof a composition according to claim 1 or 3 or a composition or mixtureof compounds according to claim
 2. 21. A pharmaceutical compositioncomprising an amount of a composition according to claim 1 or 3 or acomposition or mixture of compounds according to claim 2 effective totreat asthma in a warm-blooded animal in need of the treatment, and apharmaceutically acceptable carrier, diluent, or excipient.
 22. A methodfor treating asthma in a warm-blooded animal comprising administering toa warm-blooded animal in need thereof a therapeutically effective amountof a composition according to claim 1 or 3 or a composition or mixtureof compounds according to claim
 2. 23. A pharmaceutical compositioncomprising an amount of a composition according to claim 1 or 3 or acomposition or mixture of compounds according to claim 2 effective totreat a cough in a warm-blooded animal in need of the treatment, and apharmaceutically acceptable carrier, diluent, or excipient.
 24. A methodfor treating a cough in a warm-blooded animal comprising administrationof a therapeutically effective amount of a composition according toclaim 1 or 3 or a composition or mixture of compounds according to claim2.
 25. A pharmaceutical composition comprising an amount of acomposition according to claim 1 or 3 or a composition or mixture ofcompounds according to claim 2 effective to treat inflammation in awarm-blooded animal in need of the treatment, and a pharmaceuticallyacceptable carrier, diluent, or excipient.
 26. A method for treatinginflammation in a warm-blooded animal comprising administering to awarm-blooded animal in need thereof a therapeutically effective amountof a composition according to claim 1 or 3 or a composition or mixtureof compounds according to claim
 2. 27. A pharmaceutical compositioncomprising an amount of a composition according to claim 1 or 3 or acomposition or mixture of compounds according to claim 2 effective totreat arthritis in a warm-blooded animal in need of the treatment, and apharmaceutically acceptable carrier, diluent, or excipient.
 28. A methodfor treating arthritis in a warm-blooded animal comprising administeringto a warm-blooded animal in need thereof a therapeutically effectiveamount of a composition according to claim 1 or 3 or a composition ormixture of compounds according to claim
 2. 29. A pharmaceuticalcomposition comprising an amount of a composition according to claim 1or 3 or a composition or mixture of compounds according to claim 2effective to treat allergies in a warm-blooded animal in need of thetreatment, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 30. A method for treating allergies in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof atherapeutically effective amount of a composition according to claim 1or 3 or a composition or mixture of compounds according to claim
 2. 31.A pharmaceutical composition comprising an amount of a compositionaccording to claim 1 or 3 or a composition or mixture of compoundsaccording to claim 2 effective to treat gastrointestinal disorders in awarm-blooded animal in need of the treatment, and a pharmaceuticallyacceptable carrier, diluent, or excipient.
 32. A method for treatinggastrointestinal disorders in a warm-blooded animal comprisingadministering to a warm-blooded animal in need thereof a therapeuticallyeffective amount of a compound according to claim 1 or a compound ormixture of compounds according to claim
 2. 33. A pharmaceuticalcomposition comprising an amount of a composition according to claim 1or 3 or a composition or mixture of compounds according to claim 2effective to treat urinary incontinence in a warm-blooded animal in needof the treatment, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 34. A method for treating urinary incontinence in awarm-blooded animal comprising administering to a warm-blooded animal inneed thereof a therapeutically effective amount of a compositionaccording to claim 1 or 3 or a composition or mixture of compoundsaccording to claim
 2. 35. A pharmaceutical composition comprising anamount of a compound according to claim 1 or a compound or mixture ofcompounds according to claim 2 effective to treat irritable bowelsyndrome in a warm-blooded animal in need of the treatment, and apharmaceutically acceptable carrier, diluent, or excipient.
 36. A methodfor treating irritable bowel syndrome in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof atherapeutically effective amount of a composition according to claim 1or 3 or a composition or mixture of compounds according to claim
 2. 37.A pharmaceutical composition comprising an amount of a compositionaccording to claim 1 or 3 or a composition or mixture of compoundsaccording to claim 2 effective to treat cardiovascular diseases in awarm-blooded animal in need of the treatment, and a pharmaceuticallyacceptable carrier, diluent, or excipient.
 38. A method for treatingcardiovascular diseases in a warm-blooded animal comprisingadministering to a warm-blooded animal in need thereof a therapeuticallyeffective amount of a composition according to claim 1 or 3 or acomposition or mixture of compounds according to claim
 2. 39. Apharmaceutical composition comprising an amount of a compositionaccording to claim 1 or 3 or a composition or mixture of compoundsaccording to claim 2 effective to treat cerebral or myocardial ischemiasin a warm-blooded animal in need of the treatment, and apharmaceutically acceptable carrier, diluent, or excipient.
 40. A methodfor treating cerebral or myocardial ischemias in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof atherapeutically effective amount of a composition according to claim 1or 3 or a composition or mixture of compounds according to claim
 2. 41.A pharmaceutical composition comprising an amount of a compositionaccording to claim 1 or 3 or a composition or mixture of compoundsaccording to claim 2 effective to treat hypertension in a warm-bloodedanimal in need of the treatment, and a pharmaceutically acceptablecarrier, diluent, or excipient.
 42. A method for treating hypertensionin a warm-blooded animal comprising administering to a warm-bloodedanimal in need thereof a therapeutically effective amount of acomposition according to claim 1 or 3 or a composition or mixture ofcompounds according to claim
 2. 43. A pharmaceutical compositioncomprising an amount of a composition according to claim 1 or 3 or acomposition or mixture of compounds according to claim 2 effective totreat long-QT syndrome in a warm-blooded animal in need of thetreatment, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 44. A method for treating long-QT syndrome in a warm-bloodedanimal comprising administering to a warm-blooded animal in need thereofa therapeutically effective amount of a composition according to claim 1or 3 or a composition or mixture of compounds according to claim
 2. 45.A pharmaceutical composition comprising an amount of a compositionaccording to claim 1 or 3 or a composition or mixture of compoundsaccording to claim 2 effective to treat stroke in a warm-blooded animalin need of the treatment, and a pharmaceutically acceptable carrier,diluent, or excipient.
 46. A method for treating stroke in awarm-blooded animal comprising administering to a warm-blooded animal inneed thereof a therapeutically effective amount of a compositionaccording to claim 1 or 3 or a composition or mixture of compoundsaccording to claim
 2. 47. A pharmaceutical composition comprising anamount of a composition according to claim 1 or 3 or a composition ormixture of compounds according to claim 2 effective to treat migraine ina warm-blooded animal in need of the treatment, and a pharmaceuticallyacceptable carrier, diluent, or excipient.
 48. A method for treatingmigraine in a warm-blooded animal comprising administering to awarm-blooded animal in need thereof a therapeutically effective amountof a composition according to claim 1 or 3 or a composition or mixtureof compounds according to claim
 2. 49. A pharmaceutical compositioncomprising an amount of a composition according to claim 1 or 3 or acomposition or mixture of compounds according to claim 2 effective totreat ophthalmic diseases in a warm-blooded animal in need of thetreatment, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 50. A method for treating ophthalmic diseases in awarm-blooded animal comprising administering to a warm-blooded animal inneed thereof a therapeutically effective amount of a compositionaccording to claim 1 or 3 or a composition or mixture of compoundsaccording to claim
 2. 51. A pharmaceutical composition comprising anamount of a composition according to claim 1 or 3 or a composition ormixture of compounds according to claim 2 effective to treat diabetesmellitus in a warm-blooded animal in need of the treatment, and apharmaceutically acceptable carrier, diluent, or excipient.
 52. A methodfor treating diabetes mellitus in a warm-blooded animal comprisingadministering to a warm-blooded animal in need thereof a therapeuticallyeffective amount of a composition according to claim 1 or 3 or acomposition or mixture of compounds according to claim
 2. 53. Apharmaceutical composition comprising an amount of a compound accordingto claim 1 or a compound or mixture of compounds according to claim 2effective to treat myopathies in a warm-blooded animal in need of thetreatment, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 54. A method for treating myopathies in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof atherapeutically effective amount of a compound according to claim 1 or acompound or mixture of compounds according to claim
 2. 55. Apharmaceutical composition comprising an amount of a compound accordingto claim 1 or a compound or mixture of compounds according to claim 2effective to treat Becker's myotonia in a warm-blooded animal in need ofthe treatment, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 56. A method for treating Becker's myotonia in a warm-bloodedanimal comprising administering to a warm-blooded animal in need thereofa therapeutically effective amount of a compound according to claim 1 ora compound or mixture of compounds according to claim
 2. 57. Apharmaceutical composition comprising an amount of a compound accordingto claim 1 or a compound or mixture of compounds according to claim 2effective to treat myasthenia gravis in a warm-blooded animal in need ofthe treatment, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 58. A method for treating myasthenia gravis in a warm-bloodedanimal comprising administering to a warm-blooded animal in need thereofa therapeutically effective amount of a compound according to claim 1 ora compound or mixture of compounds according to claim
 2. 59. Apharmaceutical composition comprising an amount of a compound accordingto claim 1 or a compound or mixture of compounds according to claim 2effective to treat paramyotonia congentia in a warm-blooded animal inneed of the treatment, and a pharmaceutically acceptable carrier,diluent, or excipient.
 60. A method for treating paramyotonia congentiain a warm-blooded animal comprising administering to a warm-bloodedanimal in need thereof a therapeutically effective amount of a compoundaccording to claim 1 or a compound or mixture of compounds according toclaim
 2. 61. A pharmaceutical composition comprising an amount of acompound according to claim 1 or a compound or mixture of compoundsaccording to claim 2 effective to treat malignant hyperthermia in awarm-blooded animal in need of the treatment, and a pharmaceuticallyacceptable carrier, diluent, or excipient.
 62. A method for treatingmalignant hyperthermia in a warm-blooded animal comprising administeringto a warm-blooded animal in need thereof a therapeutically effectiveamount of a compound according to claim 1 or a compound or mixture ofcompounds according to claim
 2. 63. A pharmaceutical compositioncomprising an amount of a compound according to claim 1 or a compound ormixture of compounds according to claim 2 effective to treathyperkalemic periodic paralysis in a warm-blooded animal in need of thetreatment, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 64. A method for treating hyperkalemic periodic paralysis ina warm-blooded animal comprising administering to a warm-blooded animalin need thereof a therapeutically effective amount of a compoundaccording to claim 1 or a compound or mixture of compounds according toclaim
 2. 65. A pharmaceutical composition comprising an amount of acompound according to claim 1 or a compound or mixture of compoundsaccording to claim 2 effective to treat Thomsen's myotonia in awarm-blooded animal in need of the treatment, and a pharmaceuticallyacceptable carrier, diluent, or excipient.
 66. A method for treatingThomsen's myotonia in a warm-blooded animal comprising administering toa warm-blooded animal in need thereof a therapeutically effective amountof a compound according to claim 1 or a compound or mixture of compoundsaccording to claim
 2. 67. A pharmaceutical composition comprising anamount of a compound according to claim 1 or a compound or mixture ofcompounds according to claim 2 effective to treat autoimmune disordersin a warm-blooded animal in need of the treatment, and apharmaceutically acceptable carrier, diluent, or excipient.
 68. A methodfor treating autoimmune disorders in a warm-blooded animal comprisingadministering to a warm-blooded animal in need thereof a therapeuticallyeffective amount of a compound according to claim 1 or a compound ormixture of compounds according to claim
 2. 69. A pharmaceuticalcomposition comprising an amount of a compound according to claim 1 or acompound or mixture of compounds according to claim 2 effective to treatgraft rejection in organ transplantation or bone marrow transplantationin a warm-blooded animal in need of the treatment, and apharmaceutically acceptable carrier, diluent, or excipient.
 70. A methodfor treating graft rejection in organ transplantation or bone marrowtransplantation in a warm-blooded animal comprising administering to awarm-blooded animal in need thereof a therapeutically effective amountof a compound according to claim 1 or a compound or mixture of compoundsaccording to claim
 2. 71. A pharmaceutical composition comprising anamount of a compound according to claim 1 or a compound or mixture ofcompounds according to claim 2 effective to produce local analgesia oranesthesia in a warm-blooded animal in need thereof, and apharmaceutically acceptable carrier, diluent, or excipient.
 72. A methodfor producing local analgesia or anesthesia in a warm-blooded animal inneed thereof comprising administering to a warm-blooded animal in needthereof a therapeutically effective amount of a compound according toclaim 1 or a compound or mixture of compounds according to claim
 2. 73.A pharmaceutical composition comprising an amount of a compoundaccording to claim 1 or a compound or mixture of compounds according toclaim 2 effective to treat heart failure in a warm-blooded animal inneed of the treatment, and a pharmaceutically acceptable carrier,diluent, or excipient.
 74. A method for treating heart failure in awarm-blooded animal comprising administering to a warm-blooded animal inneed thereof a therapeutically effective amount of a compound accordingto claim 1 or a compound or mixture of compounds according to claim 2.75. A pharmaceutical composition comprising an amount of a compoundaccording to claim 1 or a compound or mixture of compounds according toclaim 2 effective to treat hypotension in a warm-blooded animal in needof the treatment, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 76. A method for treating hypotension in a warm-bloodedanimal comprising administering to a warm-blooded animal in need thereofa therapeutically effective amount of a compound according to claim 1 ora compound or mixture of compounds according to claim
 2. 77. Apharmaceutical composition comprising an amount of a compound accordingto claim 1 or a compound or mixture of compounds according to claim 2effective to treat Alzheimer's disease in a warm-blooded animal in needof the treatment, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 78. A method for treating Alzheimer's disease in awarm-blooded animal comprising administering to a warm-blooded animal inneed thereof a therapeutically effective amount of a compound accordingto claim 1 or a compound or mixture of compounds according to claim 2.79. A pharmaceutical composition comprising an amount of a compoundaccording to claim 1 or a compound or mixture of compounds according toclaim 2 effective to treat dementia in a warm-blooded animal in need ofthe treatment, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 80. A method for treating dementia in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof atherapeutically effective amount of a compound according to claim 1 or acompound or mixture of compounds according to claim
 2. 81. Apharmaceutical composition comprising an amount of a compound accordingto claim 1 or a compound or mixture of compounds according to claim 2effective to treat alopecia in a warm-blooded animal in need of thetreatment, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 82. A method for treating alopecia in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof atherapeutically effective amount of a compound according to claim 1 or acompound or mixture of compounds according to claim
 2. 83. Apharmaceutical composition comprising an amount of a compound accordingto claim 1 or a compound or mixture of compounds according to claim 2effective to enhance libido in a warm-blooded animal in need thereof,and a pharmaceutically acceptable carrier, diluent, or excipient.
 84. Amethod for enhancing libido in a warm-blooded animal in need thereofcomprising administering to a warm-blooded animal in need thereof anenhancing amount of a compound according to claim 1 or a compound ormixture of compounds according to claim
 2. 85. A composition accordingto claim 1 or 3 or a compound or mixture of compounds according to claim2, and a pharmaceutically acceptable carrier, excipient or diluent. 86.The composition according to claim 1 wherein R₁ and R₂ are takentogether with the nitrogen atom to which they are directly attached informula (I) to form a ring denoted by formula (II):

wherein the ring of formula (II) is formed from the nitrogen as shown aswell as three to nine additional ring atoms independently selected fromcarbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atomsmay be joined together by single or double bonds, and where any one ormore of the additional carbon ring atoms may be substituted with one ortwo substituents selected from hydrogen, hydroxy, C₁–C₃hydroxyalkyl,oxo, C₂–C₄acyl, C₁–C₃alkyl, C₂–C₄alkylcarboxy, C₁–C₃alkoxy, andC₁–C₂₀alkanoyloxy.
 87. The composition according to claim 86 wherein thering of formula II is a substituted or unsubstituted morpholinyl groupor a substituted or unsubstituted ketopyrrolidinyl group, wherein in thesubstituted groups any one or more of the carbon ring atoms in the ringmay be substituted with one or two substituents selected from hydrogen,hydroxy, C₁–C₃hydroxyalkyl, oxo, C₂–C₄acyl, C₁–C₃alkyl,C₂–C₄alkylcarboxy, C₁–C₃alkoxy, and C₁–C₂₀alkanoyloxy.
 88. Thecomposition according to claim 86 wherein the ring of formula II is asaturated ring.